Osteoporosis is a major medical problem that has a remarkable financial impact on society.1 Nearly one-half of all women and one-fourth of all men will sustain a fragility fracture during their lifetime.2 Hip fracture is the most serious complication of osteoporosis.
According to a recent US study, 25% of all hip fracture patients have to move to a nursing home, 50% will never achieve their previous functional capacity, and about 25% will die during the first postoperative year.3 Only 20% of patients who have sustained a previous hip fracture or other fragility fractures receive treatment for osteoporosis.4
So far there are only a few articles in the literature on the association between mortality and the use of antiosteoporotic drugs following hip fracture. A Canadian study showed a significant decrease in the mortality of patients treated with antiosteoporotic drugs versus nontreated patients.5
In a recent international large-scale, randomized, controlled multicenter trial in which hip fracture patients were randomly assigned to receive annual either zoledronic acid by intravenous infusion or a placebo infusion, the secondary endpoint was all-cause mortality.6 Both groups received daily oral calcium and vitamin D. The median follow-up was 1.9 years. In the zoledronic acid group, there was a relative risk reduction of 28% for death from any cause.6
In 2010, four articles showing an association between antiosteoporotic treatment and reduced all-cause mortality were published.7–10 In a nested case-control study from Australia with a 5-year follow-up time, bisphosphonate use was associated with reduced mortality after hip fracture (p = .002).7 In a Canadian randomized 3-year follow-up study, hip fracture patients with oral bisphosphonate use had a lower mortality than those receiving no treatment (7% versus 16%).8 Each year of treatment was associated with a 63% relative reduction in the risk of death.8 Another Australian 5-year follow-up study among institutionalized hip fracture patients showed that the use of oral bisphosphonates was associated with a 27% reduction in the risk of death compared with nonusers.9 In a recent meta-analysis by Bolland and colleagues10 on the effect of osteoporosis treatment on mortality, eight studies of four drugs (ie, risedronate, strontium ranelate, zoledronic acid, and denosumab) were included in the primary analysis and two alendronate studies in the secondary analysis. In the primary analysis, treatment was associated with an 11% reduction in mortality. In the secondary analysis, the results were similar.10
In our previous study, 221 new hip fracture patients treated in 2003–2004 at two acute hospitals were followed for 4 years.11 After a median of 27.5 months from the fracture, a questionnaire was sent to all patients who were still alive at that time concerning their use of prescribed calcium plus vitamin D supplementation and of antiosteoporotic drugs. Data on the use of these two drugs also were checked against information on reimbursement of drug prescriptions held by the Finnish Social Insurance Institution. Patients' survival was analyzed using both Bayesian multivariate analysis and the life-table method. The results indicated a positive association between mortality and the use of prescribed calcium plus vitamin D in both genders, as well as with concomitant use of antiosteoporotic drugs in females.11 These new results needed to be verified with a larger data pool.
The aim of this study was to investigate the association of the postfracture use of prescribed calcium plus vitamin D or vitamin D supplementation and the postfracture use of antiosteoporotic drugs with the survival of hip fracture patients using nationwide register-based data in Finland (latitude 60 to 70°N), which has a population of 5.3 million.
Material and Methods
This study was based on the Finnish PERFormance, Effectiveness and Cost of Treatment episodes (PERFECT) hip fracture research database,12 which contains data from several nationwide administrative registers, including the Hospital Discharge Register maintained by the National Institute for Health and Welfare, the Causes-of-Death Register of Statistics Finland, and the Special Reimbursement Register and prescription database maintained by the Social Insurance Institution.
The hip fracture cohort was formed by identifying persons who had a hospital discharge with a primary or secondary diagnosis of a new hip fracture [International Classification of Diseases, revision 10 (ICD-10) codes S72.0, S72.1, and S72.2] during the years 2000–2007. Background and follow-up data for the cohort were extracted from the above-mentioned registers by using unique personal identity codes, which made deterministic record linkage possible. Background information included sex, age, comorbidities, and prior care. The index date for each hip fracture was the admission day to a surgical ward because of a new hip fracture.13 Register-based data have been found to be suitable for hip fracture follow-up studies.14
In order to homogenize the study population, patients younger than 50 years of age and patients with a previous hip fracture were excluded. Since the nationwide database does not contain data on medications during hospitalization, the data were further restricted to patients who were discharged home within 4 months of hip fracture during the years 2000–2007 [ie, patients who died before discharge or who became long-term-care patients (had a care episode lasting more than 4 months) were excluded]. This guaranteed the availability of appropriate medication purchase data and a follow-up period of at least 1 year for each patient. Our research data comprise a rather homogeneous patient population for which the consideration of prescriptions for osteoporosis-related medication is of primary importance.
The medications of interest were divided into two groups: antiosteoporotic drugs and calcium plus vitamin D or vitamin D supplements. Antiosteoporotic drugs were identified using Anatomical Therapeutic Chemical (ATC) classification codes and included bisphosphonates (ATC: M05B), estrogen (ATC: G03C), teriparatide (ATC: H05AA), calcitonin (ATC: H05BA), and selective estrogen receptor modulators (ATC: G03XC). Reimbursed purchases of prescribed vitamin D supplements (ATC: A11CB and A11CC) and calcium plus vitamin D supplements (ATC: A12AX) also were identified using ATC codes. During the study period, there were only four different preparations of prescribed calcium (500 mg) plus vitamin D (400 IU) supplements available in Finland. These drugs contained calcium in the form of calcium carbonate.
In descriptive analyses, the patient was determined as a user of medication if he or she purchased medication during the first 3 months of discharge home. Univariate comparisons between the characteristics of patients in different populations were performed by using t tests and chi-square tests. Unadjusted cumulative mortality was calculated by using the Kaplan-Meier estimator. Hazard ratios (HRs) were estimated using Cox's proportional hazards regression model with a robust variance estimator. The model allowed adjustment for confounding factors such as age, sex, fracture type, operative method, comorbidities, prior care and medication use, and fracture year. Tests and graphic diagnostics for proportional hazards were performed with the help of the scaled Schoenfeld residuals. Stratification allowing different baseline hazard functions was used if the proportionality assumption did not hold for some factors. In order to further adjust for potential bias caused by the death of a patient before he or she purchased prescribed medication, time-dependent covariates for the whole follow-up time were used in models dealing with postdischarge medication. The time-dependent covariates were zero until the day of medication purchase and one thereafter until the end of the follow-up. Data were processed and analyzed using the statistical software packages SAS Version 9.1 (www.sas.com) and R Version 2.8.1 (www.r-project.org).
A total of 23,615 patients were discharged home after hip fracture, which is 70% of all hip fracture patients aged 50 years or older who lived at home at the time of the fracture in Finland during 2000–2007. The percentage of men was similar (29%) in both groups. However, patients discharged home were younger and had fewer comorbidities, and their short-term mortality after hip fracture was significantly lower (Table 1). One-year cumulative mortality after discharge home decreased significantly from 10.3% in the period 2000–2003 to 9.5% in the period 2004–2007, corresponding to a hazard ratio (HR) of 0.89 [95% confidence interval (CI) 0.82–0.97, p = .007] after adjustment for the factors listed in Table 2. Further adjustment for medication after discharge home yielded a borderline significant HR of 0.92 (95% CI 0.84–1.00, p = .05).
Table 1. Background Information on Hip Fracture Patients Aged ≥ 50 Years Living at Home at the Time of Fracture in Finland, 2000–2007
All hip fracture patients in Finland living at home at the time of fracture
Patients discharged home after hip fracture (research data)
Number of patients
Age, mean (SD)
Age, women, mean (SD)
Age, men, mean (SD)
Type of fracture, %
Neck of femur
Operative method, %
Hemiprosthesis (without cement)
Total hip prosthesis
Hospital days during 3 months preceding the fracture, mean (SD)
Mental health disorders
Other degenerative brain diseases
Becomes a long-term patient
Table 2. Background Information on Hip Fracture Patients Aged ≥ 50 Years Who Were Living at Home at the Time of Fracture and Were Discharged Home After Hip Fracture in Finland, 2000–2007
Purchases/no purchases of antiosteoporotic drugs and/or calcium plus vitamin D or vitamin D supplements during 3 months after discharge home.
Number of patients
Age, mean (SD)
Age, women, mean (SD)
Age, men, mean (SD)
Type of fracture, %
Neck of femur
Operative method, %
Hemiprosthesis (without cement)
Total hip prosthesis
Hospital days during 3 months preceding the fracture, mean (SD)
Length of stay before discharge home, mean (SD)
Mental health disorders
Other degenerative brain diseases
Glucocorticoid purchases during the year preceding the hip fracture, %
Purchases of antiosteoporotic drugs and/or calcium plus vitamin D or vitamin D supplements during the year preceding the hip fracture, %
The proportion of patients who purchased prescribed calcium plus vitamin D or vitamin D supplements among all hip fracture patients discharged home increased during the years 2000–2005, but after that there was a significant drop to the same level as in 2003. The proportion of patients who purchased bisphosphonates increased until 2004, and after that, the figures have remained about the same or somewhat lower. For calcitonin and estrogen, the proportions have remained about the same (Fig. 1).
The proportion of calcium plus vitamin D or vitamin D supplement users was almost twice as high among women as among men; for antiosteoporotic drugs, the difference was even greater. In 2007, the purchase rates of calcium plus vitamin D or vitamin D supplements and of the most common antiosteoporotic drugs (ie, bisphosphonates) were, respectively, 13% and 8% in males and 22% and 27% in females (Fig. 1).
There were a number of differences in the background factors among patients who purchased calcium plus vitamin D or vitamin D supplements or antiosteoporotic drugs compared with those who did not purchase these medications (Table 2). The proportion of men was much higher among nonpurchasers of medication than among purchasers (35% versus 15%), and medication purchases during the year preceding hip fracture were, as expected, lower among patients who did not purchase antiosteoporotic drugs or calcium plus vitamin D or vitamin D supplements than among those who did after discharge home (9% versus 43%). A closer look at men who purchased these medications (n = 1009) showed that they were in significantly poorer health than those who did not make purchases (n = 5844). They suffered more often from rheumatic diseases, stroke, cancer, chronic obstructive pulmonary disease (COPD)/asthma, and depression. They also purchased more glucocorticoid and spent more days in hospital prior to the fracture.
Unadjusted 1-year mortality after discharge home was significantly lower among patients who purchased calcium plus vitamin D or vitamin D supplements or antiosteoporotic drugs compared with those who did not purchase these medications (HR = 0.74, 95% CI 0.67–0.81, p < .001). The corresponding HRs were 0.89 (95% CI 0.74–1.07, p = .21) for men and 0.77 (95% CI 0.69–0.86, p < .001) for women. For purchasers of calcium plus vitamin D or vitamin D supplements, HR was 0.74 (95% CI 0.66–0.83, p < .001), and for purchasers of antiosteoporotic drugs, HR was 0.69 (95% CI 0.62–0.77, p < .001). The difference in unadjusted cumulative mortality remained significant for the whole 8-year-follow-up period for antiosteoporotic drugs, but for calcium plus vitamin D or vitamin D supplements, the significant difference could no longer be demonstrated after 5 years (Fig. 2).
After adjustment for the factors listed in Table 2 and the year, the postfracture use of calcium plus vitamin D or vitamin D supplements alone was significantly associated with lower 1-year mortality among men, whereas among women the use of antiosteoporotic drugs alone was significantly associated with lower mortality. Survival in both genders was even better if calcium plus vitamin D or vitamin D supplements and antiosteoporotic drugs were used concomitantly (Table 3).
Table 3. Medication Purchase-Specific Hazard Ratios for 1-Year Mortality Among Patients Discharged Home After Hip Fracture, Cox's Proportional Hazards Regression With Time-Dependent Covariates for Medication Purchases, Adjusted for Age, Type of Fracture, Operative Method, Hospital Days Preceding the Fracture, Length of Stay Before Discharge Home, Comorbidities, Year, and Purchases of Glucocorticoids and Antiosteoporotic Drugs and Calcium Plus Vitamin D or Vitamin D Supplements During the Year Preceding the Hip Fracture
Medication purchases after discharge home
No purchases of antiosteoporotic drugs or calcium plus vitamin D or vitamin D supplements
Only purchases of antiosteoporotic drugs
Only purchases of calcium plus vitamin D or vitamin D supplements
Purchases of antiosteoporotic drugs and calcium plus vitamin D or vitamin D supplements
The total number needed to treat (NNT) among those hip fracture patients who used calcium plus vitamin D or vitamin D supplements and/or antiosteoporotic medication was 1/(0.8910.74 – 0.891) = 37 for 1-year follow-up (95% CI 29–51).
In this study, we used a nationwide database to evaluate antiosteoporotic treatment in hip fracture patients. The study shows a low and even decreasing rate in purchasers of prescribed calcium plus vitamin D or vitamin D supplementation and antiosteoporotic drugs in Finland (Fig. 1) despite the recommendations stated in national guidelines.15 Many previous studies have shown undertreatment of osteoporosis following hip fracture in the elderly,16 although hip fractures generally are regarded as the most serious manifestation of osteoporosis and are associated with remarkable morbidity and mortality.1
This study detected a significant decrease in the 1-year mortality of treated versus untreated patients. The postfracture use of prescribed calcium plus vitamin D or vitamin D supplements in men and the use of antiosteoporotic drugs in women were associated with lower mortality. The highest survival was achieved when calcium plus vitamin D or vitamin D supplements and antiosteoporotic drugs were used simultaneously.
There are a few indications pointing to a possible link between the use of prescribed calcium plus vitamin D supplements and/or antiosteoporotic drugs and mortality in hip fracture patients. Our recent Finnish study11 suggested a relationship between postfracture use of calcium plus vitamin D and reduced mortality among hip fracture patients, and this study detected similar results for males. Further, in our previous study,11 the survival in women was even better if calcium plus vitamin D supplements and antiosteoporotic drugs were used simultaneously. This finding was replicated in this study.
The mechanism by which deaths potentially can be prevented with calcium plus vitamin D and antiosteoporotic treatment is not clear. Prevention of new fractures may be one explanation. According to Kanis and colleagues,17 17% to 32% of deaths (depending on age) after hip fracture were causally related to the fracture. In the zoledronic acid study by Colon-Emeric and colleagues,18 subsequent fractures were significantly associated with death (HR = 1.72, 95% CI 1.17–2.51) but explained only 8% of the zoledronic acid effect. Zoledronic acid also may have an effect on cardiovascular events and pneumonia,18 and fracture prevention seems to explain only a minor proportion of the mortality reduction.
One reason for the better postfracture survival of medication users may have been the use of prescribed calcium plus vitamin D. In addition to an increased risk of osteoporosis,19 vitamin D insufficiency appears to be associated with cancers,20 muscle weakness,21 respiratory infections,22 autoimmune diseases,23 diabetes,24 and cardiovascular diseases.25 The recent literature includes a number of studies showing an association between 25-hydroxyvitamin D levels and the risk of mortality in the general population. A low level (<50 nmol/L) is independently associated with all-cause and cardiovascular mortality.26 Ginde and colleagues27 showed that low serum 25-hydroxyvitamin D level (<50 nmol/L) appears to be the highest risk for all-cause mortality in older US adults, but levels of 100 nmol/L or higher may be necessary for better survival. On the other hand, a too high serum 25-hydroxyvitamin D level (>125nmol/L) in women or a too low level (<44.5 nmol/L) in the general population has been a higher risk of mortality, whereas levels of 75 to 122.5 nmol/L showed a lower risk of mortality.28
In the Women's Health Initiative, calcium–vitamin D randomized, controlled trial participants (51 to 82 years of age) received calcium (1000 mg) plus vitamin D (400 IU) supplementation daily or a placebo with an average follow-up of 7 years.29 The calcium plus vitamin D supplementation did not have a statistically significant effect on mortality rates, but the findings support the possibility that these drugs may reduce mortality rates in postmenopausal women.29 A recent Swedish study showed a positive association in men between high intake of dietary calcium (mean 1953 mg/d) and all-cause mortality versus low intake (mean 990 mg/d, p < .001).30
There are also some studies on a negative effect of supplemental use of calcium. In a study from New Zealand including 1471 postmenopausal women (mean age 74 years), 732 were randomized to receive calcium (1000 mg) supplementation and 739 to receive a placebo in a 5-year follow-up.31 Myocardial infarction was reported more commonly in the calcium group than in the control group (p = .01).31 This randomized, controlled trial shed doubt on the benefits of calcium supplements owing to their possible harmful cardiovascular effects. A recent meta-analysis by Bolland and colleagues32 on the effect of calcium supplements (without vitamin D) on the risk of myocardial infarction and cardiovascular events (15 randomized, placebo-controlled trials) showed an association with an increase of about 30% in the incidence of myocardial infarction.32
In this study, antiosteoporotic drugs were defined as bisphosphonates (ie, alendronate, risedronate, ibandronate, etidronate, and raloxifene), teriparatide, nasal calcitonin, and estrogen. Other antiosteoporotic drugs were not available during the study period in Finland. Most of the hip fracture patients in the present Finnish nationwide database study used bisphosphonates, mainly alendronate. In a recent nationwide register study from Norway on patients aged 40 years or older who received antiosteoporotic drugs for osteoporosis during 2004–2007, 88% used alendronate in 2007.33 The incidence of the overall use of bisphosphonates decreased in Norway from 2005 to 2007.33 A similar result was found in this study. The increase in the use of calcium plus vitamin D and antiosteoporotic drugs in Finland during 2001–2004 was caused by the introduction of the first Finnish national guidelines on osteoporosis34 and many regional instruction courses that were held during the years in question.
The side effects of bisphosphonates include osteonecrosis of the jaw,35 esophageal irritation, musculoskeletal pain, subtrochanteric femoral stress fractures (alendronate),36 and atrial fibrillation.37 According to a recent published secondary analysis using the results of three randomized bisphosphonate trials (n = 14,195), the occurrence of fractures of the subtrochanteric or diaphyseal femur was rare, even in women with osteoporosis who received bisphosphonates for up to 10 years.38
We can learn much about these side effects, but the risk-benefit balance of bisphosphonates in patients with osteoporosis remains strongly positive. According to a review on the long-term use of bisphosphonates in osteoporosis, the researchers concluded that these drugs offer a safe and effective treatment to reduce fracture risk.39 The authors recommend a drug holiday after 5 to 10 years of bisphosphonate treatment.39 The duration of treatment and the length of the break should be tailored to individual patient circumstances.39
Our study has some limitations. First of all, the study was observational because it was based on register data, and the study design cannot confirm whether the detected association between the prescribed calcium plus vitamin D or vitamin D supplements and/or antiosteoporotic drugs and mortality in patients with hip fractures is causal or not. It is therefore possible that patients on medication may have a somewhat better health status or clinical judgment of a better prognosis or, vice versa, that patients taking several drugs for serious diseases are less likely to get prescriptions for osteoporosis medication. Restricting this study to patients who were discharged home after the hip fracture should, however, homogenize the population and protect against this kind of confounding bias.
So far there are only a few centers in Finland that have established specific programs for coordinating the care of patients with fragility fractures to optimize antiosteoporotic treatment. Finnish orthopedic and trauma surgeons and general practitioners are mainly poorly aware of the scope of the problems associated with osteoporotic fractures, and the national osteoporosis guidelines are poorly followed. According to the Finnish guidelines,15, 34 all hip fracture patients discharged home should take supplements containing calcium 500 mg plus vitamin D 400 IU twice a day, and aged patients (70 to 75 years old) should take antiosteoporotic medication simultaneously. In younger patients, bone mineral density measurement should be performed before starting antiosteoporotic treatment. Causes of secondary osteoporosis should be excluded by laboratory tests. However, the use rate of these drugs in Finland is low. Moreover, osteoporosis treatment of hip fracture patients seems to vary from one Finnish hospital district region to another (unpublished data). We do not believe that the users of these medications were selected in this study because their prognosis was better. More probably, possible selection could have arisen owing to the variation in regional treatment policies.
We only had information on the reimbursed medication purchases and no information on how long these drugs were used and whether the patients used calcium plus vitamin D or vitamin D supplements once or twice daily. In addition, it is possible that some persons may have purchased calcium plus vitamin D or vitamin D supplements but have not received reimbursement because these medications are quite cheap. However, that is unlikely because there still remains a financial incentive to buy prescribed medication that will be partly reimbursed. Moreover, according to our previous study among hip fracture patients, the daily doses of the nonprescribed calcium plus vitamin D supplements were very low (calcium 520 mg and vitamin D 300 IU).16 In our previous study, we found that half the patients with a new hip fracture suffered from hypovitaminosis D (<37.5 nmol/L) and 9% from severe hypovitaminosis D (<20 nmol/L).40 The serum vitamin D levels among Finns are, on average, poor.41
Adherence to oral antiosteoporotic treatment is problematic. Although we do not know the adherence to the calcium plus vitamin D or vitamin D supplementation and/or oral antiosteoporotic treatment in this study, some facts about these drugs are known. The therapeutic effect of bisphosphonates, which were used mainly in this study, persists for many years. Pharmacokinetic studies show that bisphosphonates remain in bone matrix for many years and that their terminal half-life is similar to that of bone (10.5 years).42 The half-life of serum 25-hydroxyvitamin D is only 15 days.43 Following ingestion of calcium carbonate, the ionized calcium concentration reaches its peak level in just 3 hours.44
In order to protect for confounding bias, we adjusted the results for observed confounders and used time-dependent covariates for medication variables. We also performed sensitivity analyses with different follow-up times and factors to be adjusted. It turned out that the detected associations between the calcium plus vitamin D or vitamin D and/or oral antiosteoporotic medication and mortality were robust for women. For men, the situation was more complicated, and the results were sensitive to follow-up time and also to the calcium plus vitamin D or vitamin D and/or oral antiosteoporotic medication taken before the hip fracture. Our interpretation is that a large proportion of antiosteoporotic medication purchases for men, especially if not made directly after the hip fracture, are because of cancer or the use of oral cortisone and therefore reflect the (incompletely observed) risk factors leading to medication rather than the actual effects of medication. Such phenomena complicate statistical analysis, and the results for men therefore must be interpreted with caution.
We also adjusted for year in our analyses because we wanted to be sure that the observed effects are not explained by decreasing mortality among hip fracture patients during the time of the study in tandem with somewhat increasing use of medication. Unfortunately, we cannot exclude the potential biasing effect of some unobserved confounders, such as socioeconomic position. It also has been suggested that the so-called healthy adherer effect may have a role in the mortality association because it is possible that adherence to drug therapy works as a surrogate marker for overall healthy behavior.45 In this study, that would indicate strong inequalities in the treatment, that is, that a selection of especially healthy persons also would receive better care than others in the relatively healthy population of hip fracture patients who were discharged home after the fracture. This should not be the case in Finland because all Finnish citizens suffering from hip fracture use the same tax-funded public health care system.
It also must be noted that we could not study survival in non–hip fracture patients taking prescribed calcium plus vitamin D supplements or antiosteoporotic medication because our cohort included only hip fracture patients. Furthermore, we could not assess alternative outcomes, such as falls, whose risk is known to be reduced with a sufficient intake of vitamin D (700 to 1000 IU/d),21 because of the limitations of the Hospital Discharge Register on which our data were based. These issues should be studied further with other data sets that include the required information.
The strengths of this study lie in the large number of unselected patients (n = 23,615). In fact, all hip fracture patients in Finland discharged home after fracture during the study period were included in the study population, and the results reflect the effects of treatment in practice for the unselected total population. Also, complete follow-up data and the most important background characteristics, including data on comorbidities, were available for this cohort, and the quality of Finnish register data for hip fracture follow-up studies is shown to be very good.14 Moreover, the study design was rather conservative, and it was not likely that any weak effects could have been detected by using 1-year mortality as an outcome among the home-discharged hip fracture patients.
In conclusion, hip fractures are known to cause substantial morbidity and mortality, and effective osteoporosis treatment prevents secondary fractures. According to this study, there is an association between medical treatment of osteoporosis and reduction in postfracture mortality in hip fracture patients. This result supports the interpretation that this potentially effective treatment should be put into practice more widely.
PL has received a speaker's fee or paid traveling expenses from Amgen, GlaxoSmithKline, MSD, Novartis, Roche, and Sanofi-Aventis. All the other authors state that they have no conflicts of interest.
The work of Reijo Sund was supported financially by the Yrjö Jahnsson Foundation (Grant 5978).