Baseline health-related quality of life predicts falls: a secondary analysis of a randomized controlled trial.

PURPOSE: Among older adults, health-related quality of life (HRQoL) and falls are associated. Generic patient-reported outcomes measures (PROMs) assess individual's HRQoL. The role for PROMs, a potential tool for predicting subsequent falls, remains under-explored. Our primary aim was to determine whether a baseline PROMs assessment of HRQoL may be a useful tool for predicting future falls. METHODS: A secondary analysis of a 12-month randomized clinical trial (RCT) of a home-based exercise program among 344 adults (67% female), aged ≥ 70 years, with ≥ 1 falls in the prior year who were randomized (1:1) to either a home-based exercise program (n = 172) or usual care (n = 172). A negative binomial regression model with total falls count as the dependent variable evaluated the main effect of the independent variable-baseline HRQoL (measured by the Short-Form-6D)-controlling for total exposure time and experiment group (i.e., exercise or usual care) for the total sample. For the usual care group alone, the model controlled for total exposure time. RESULTS: For the total sample, the rate of subsequent total falls was significantly predicted by baseline HRQoL (IRR = 0.044; 95% CI [0.005-0.037]; p = .004). For the usual care group, findings were confirmed with wider confidence intervals and the rate of prospective total falls was significantly predicted by baseline HRQoL (IRR = 0.025; 95% CI [0.001-0.909]; p = .044). CONCLUSION: These findings suggest the ShortForm-6D should be considered as part of falls prevention screening strategies within a Falls Prevention Clinic setting. Trial Registrations ClinicalTrials.gov Protocol Registration System. Identifier: NCT01029171; URL: https://clinicaltrials.gov/ct2/show/NCT01029171 . Identifier: NCT00323596; URL: https://clinicaltrials.gov/ct2/show/NCT00323596 .

Effect of a Home-Based Exercise Program on Subsequent Falls Among Community-Dwelling High-Risk Older Adults After a Fall: A Randomized Clinical Trial.

Importance: Whether exercise reduces subsequent falls in high-risk older adults who have already experienced a fall is unknown. Objective: To assess the effect of a home-based exercise program as a fall prevention strategy in older adults who were referred to a fall prevention clinic after an index fall. Design, Setting, and Participants: A 12-month, single-blind, randomized clinical trial conducted from April 22, 2009, to June 5, 2018, among adults aged at least 70 years who had a fall within the past 12 months and were recruited from a fall prevention clinic. Interventions: Participants were randomized to receive usual care plus a home-based strength and balance retraining exercise program delivered by a physical therapist (intervention group; n = 173) or usual care, consisting of fall prevention care provided by a geriatrician (usual care group; n = 172). Both were provided for 12 months. Main Outcomes and Measures: The primary outcome was self-reported number of falls over 12 months. Adverse event data were collected in the exercise group only and consisted of falls, injuries, or muscle soreness related to the exercise intervention. Results: Among 345 randomized patients (mean age, 81.6 [SD, 6.1] years; 67% women), 296 (86%) completed the trial. During a mean follow-up of 338 (SD, 81) days, a total of 236 falls occurred among 172 participants in the exercise group vs 366 falls among 172 participants in the usual care group. Estimated incidence rates of falls per person-year were 1.4 (95% CI, 0.1-2.0) vs 2.1 (95% CI, 0.1-3.2), respectively. The absolute difference in fall incidence was 0.74 (95% CI, 0.04-1.78; P = .006) falls per person-year and the incident rate ratio was 0.64 (95% CI, 0.46-0.90; P = .009). No adverse events related to the intervention were reported. Conclusions and Relevance: Among older adults receiving care at a fall prevention clinic after a fall, a home-based strength and balance retraining exercise program significantly reduced the rate of subsequent falls compared with usual care provided by a geriatrician. These findings support the use of this home-based exercise program for secondary fall prevention but require replication in other clinical settings. Trial Registration: ClinicalTrials.gov Identifiers: NCT01029171; NCT00323596.

Are the EQ-5D-3L and the ICECAP-O responsive among older adults with impaired mobility? Evidence from the Vancouver Falls Prevention Cohort Study.

PURPOSE: Preference-based generic measures are gaining increased use in mobility research to assess health-related quality of life and wellbeing. Hence, we examined the responsiveness of these two measures among individuals at risk of mobility impairment among adults aged ≥70 years. METHODS: We conducted a 12-month prospective cohort study of community-dwelling older adults (n = 288 to n = 341 depending on analysis) who were seen at the Vancouver Falls Prevention Clinic who had a history of at least one fall in the previous 12 months. We compared the responsiveness of the EuroQol-5 Domain-3 Level (EQ-5D-3L) and the index of capability for older adults (ICECAP-O) by examining changes in these measures over time (i.e., over 6 and 12 months) and by examining whether their changes varied as a function of having experienced 2 or more falls over 6 and 12 months. RESULTS: Only the ICECAP-O showed a significant change over time from baseline through 12 months; however, neither measure showed change that exceeded the standard error of the mean. Both measures were responsive to falls that occurred during the first 6 months of the study (p < .05). These effects appeared to be amplified among individuals identified as having mild cognitive impairment (MCI) at baseline (p < .01). Additionally, the EQ-5D-3L was responsive among fallers who did not have MCI as well as individuals with MCI who did not fall (p < .05). CONCLUSION: This study provides initial evidence suggesting that the EQ-5D-3L is generally more responsive, particularly during the first 6 months of falls tracking among older adults at risk of future mobility impairment.

Audit of Atypical Femoral Fractures and a Description of Some of Their Features.

PURPOSE: Atypical femoral fractures (AFF) are recently described events related to osteoporosis and, potentially, a rare result of antiresorptive treatment. METHODS: We set out to audit the diagnosis of AFF in an acute hospital. Charts and radiographs were reviewed retrospectively from patients diagnosed with subtrochanteric femoral fractures according to hospital discharge coding at Vancouver General Hospital (VGH), Canada, from January 2005 to March 2013. RESULTS: A total of 3084 patients were discharged from the hospital with a diagnosis of hip fracture between 2005 and 2013. Of these, 204 were coded as having had subtrochanteric fractures; 178 of the patients thus coded had radiographic evidence of other fracture types-usually intertrochanteric fractures. Eleven patients did not have available radiographs. Of the remaining 193 patients whose radiographs were reviewed, 24 (12.4%) fulfilled the published criteria for AFF. OUR OBSERVATIONS WERE: 1) laterality: 13 of 24 AFF (54.2%) were right-sided; 2) there was only one incomplete AFF in this series: a completed fracture was an inclusion criterion, but 1 patient with an AFF had both that fracture and an incomplete fracture and further foci of periosteal or endosteal foci of new bone (PENB) involving the contralateral femur; 3) radiologists had only diagnosed AFF in only 1 of the 24 patients with characteristic radiographic signs of AFF; 4) all but 1 patient had a focus of periosteal and/or endosteal new bone (PENB) through which the fracture line invariably passed, and in the 1 exception the radiography was too poor to be sure of this but there was a symmetrical contralateral focus of PENB; 5) in 19 of 24 patients there was an adequate image of part of the contralateral femur and of these 12 (63%) had a contralateral focus of PENB situated ±2.5 cm from the index lesion site when measured from the upper aspect of the greater trochanter, and in another patient a prior fracture of the contralateral femur had been treated surgically and it was at a symmetrical contralateral location from the index fracture.; 6) in 3 of the 19 patients multiple foci of PENB were detected on the lateral aspect of the contralateral femur even though the examination was of limited extent; and 7) AFFs were associated with bisphosphonate medication in 75% of the patients studied. CONCLUSIONS: Hospital discharge coding misclassified a great majority of femoral fractures as subtrochanteric. As an essential criteria for diagnosing AFF is their subtrochanteric location, this misclassification impaired our ability to retrospectively search for AFF patients. Radiologists tended not to report AFF when typical radiographic characteristics were present. Bilateral and multifocal disease is of interest in pointing to the diagnosis and in suggesting that the mechanism of injury in respect of these unusual fractures is more complex than simple low-energy trauma.

Understanding and communicating the benefits and risks of denosumab, raloxifene, and teriparatide for the treatment of osteoporosis.

The number needed to treat is a valuable metric to determine the benefit of therapy, but it must be viewed against the respective number needed to harm. Denosumab and teriparatide (TPTD) have proven antifracture efficacy at vertebral and nonvertebral sites, whereas raloxifene has proven antifracture efficacy at the spine only. Denosumab use has been associated with a small, yet statistically significant, increased incidence of eczema and serious cellulitis. Raloxifene use has been associated with statistically significant increases in the risk of venous thromboembolism and possibly deadly stroke, although not an increase in total strokes. No significant, nontransient adverse events have been reported with TPTD use. When used for the treatment of postmenopausal osteoporosis, denosumab, raloxifene, and TPTD all generally have favorable risk-to-benefit profiles, but therapy-specific contraindications necessitate thoughtful consideration of all available clinical information and individualization of treatment decisions.

High-resolution peripheral quantitative computed tomography for the assessment of bone strength and structure: a review by the Canadian Bone Strength Working Group.

Bone structure is an integral determinant of bone strength. The availability of high resolution peripheral quantitative computed tomography (HR-pQCT) has made it possible to measure three-dimensional bone microarchitecture and volumetric bone mineral density in vivo, with accuracy previously unachievable and with relatively low-dose radiation. Recent studies using this novel imaging tool have increased our understanding of age-related changes and sex differences in bone microarchitecture, as well as the effect of different pharmacological therapies. One advantage of this novel tool is the use of finite element analysis modelling to non-invasively estimate bone strength and predict fractures using reconstructed three-dimensional images. In this paper, we describe the strengths and limitations of HR-pQCT and review the clinical studies using this tool.

Comparing the cost-effectiveness of the Otago Exercise Programme among older women and men: A secondary analysis of a randomized controlled trial.

OBJECTIVE: Using stratified analyses, we examined the cost-effectiveness of the Otago Exercise Programme (OEP), from a health care system perspective, among older women and men who have previously fallen. METHODS: This study was a secondary stratified analysis (by women and men), of a 12-month prospective economic evaluation of a randomized clinical trial (OEP compared with usual care). Three hundred and forty four community-dwelling older adults (≥70; 172 OEP (110 women; 62 men), 172 usual care (119 women; 53 men)) who sustained a fall in the past 12 months and received a baseline assessment at the Vancouver Falls Prevention Clinic, Canada were included. A gender by OEP/usual care interaction was examined for the falls incidence rate ratio (IRR). Outcome measures stratified by gender included: falls IRR, incremental cost-per fall prevented (ICER), incremental cost per quality adjusted life year (QALY, ICUR) gained, and mean total health care resource utilization costs. RESULTS: Men were frailer than women at baseline. Men incurred higher mean total healthcare costs $6794 (SD: $11906)). There was no significant gender by OEP/usual care interaction on falls IRR. The efficacy of the OEP did not vary by gender. The adjusted IRR for the OEP group demonstrated a 39% (IRR: 0.61, CI: 0.40-0.93) significant reduction in falls among men but not women (32% reduction (IRR: 0.69, CI: 0.47-1.02)). The ICER showed the OEP was effective in preventing falls and less costly for men, while it was costlier for women by $42. The ICUR showed the OEP did not impact quality of life. CONCLUSION: Future studies should explore gender factors (i.e., health seeking behaviours, gender related frailty) that may explain observed variation in the cost-effectiveness of the OEP as a secondary falls prevention strategy. TRIAL REGISTRATIONS: ClinicalTrials.gov Protocol Registration System Identifier: NCT01029171; URL: https://clinicaltrials.gov/ct2/show/NCT01029171 Identifier: NCT00323596; URL: https://clinicaltrials.gov/ct2/show/NCT00323596.

Exercise, Processing Speed, and Subsequent Falls: A Secondary Analysis of a 12-Month Randomized Controlled Trial.

BACKGROUND: Strength and balance retraining exercises reduce the rate of subsequent falls in community-dwelling older adults who have previously fallen. Exercise can also improve cognitive function, including processing speed. Given processing speed predicts subsequent falls, we aimed to determine whether improved processing speed mediated the effects of the Otago Exercise Program on the rate of subsequent: (i) total falls, (ii) non-injurious falls, (iii) moderate injurious falls, and (iv) serious injurious falls. METHOD: A secondary complete case analysis of a 12-month, single-blind, randomized clinical trial among 256 of 344 adults aged at least 70 years who fell in the previous 12 months. Participants were randomized 1:1 to receive usual care plus the Otago Exercise Program (n = 123) or usual care (n = 133), consisting of fall prevention care provided by a geriatrician. The primary outcome was self-reported number of falls over 12 months (ie, rate of falls). Processing speed was assessed at baseline and at 12 months by the Digit Symbol Substitution Test (DSST). Causal mediation analyses were conducted using quasi-Bayesian estimates and 95% confidence intervals. RESULTS: Exercise significantly reduced the rate of subsequent moderate injurious falls (IRR = 0.49; 95% CI: 0.31, 0.77; p = .002) and improved processing speed (estimated mean difference: 1.16 points; 95% CI: 0.11, 2.21). Improved DSST mediated the effect of exercise on the rate of subsequent moderate injurious falls (estimate: -0.06; 95% CI: -0.15, -0.001; p = .036). CONCLUSION: Improved processing speed may be a mechanism by which exercise reduces subsequent moderate injurious falls in older adults who fell previously. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov Protocol Registration System:NCT01029171: https://clinicaltrials.gov/ct2/show/NCT01029171NCT00323596: https://clinicaltrials.gov/ct2/show/NCT00323596.

Action Seniors! Cost-Effectiveness Analysis of a Secondary Falls Prevention Strategy Among Community-Dwelling Older Fallers.

BACKGROUND: The Otago Exercise Program (OEP) has demonstrated cost-effectiveness for the primary prevention of falls in a general community setting. The cost-effectiveness of exercise as a secondary falls prevention (ie, preventing falls among those who have already fallen) strategy remains unknown. The primary objective was to estimate the cost-effectiveness (incremental cost-effectiveness/utility ratio) of the OEP from a healthcare system perspective. DESIGN: A concurrent 12-month prospective economic evaluation conducted alongside the Action Seniors! randomized critical trial (OEP compared with usual care). SETTING: Vancouver Falls Prevention Clinic (Vancouver, BC, Canada; http://www.fallsclinic.ca). PARTICIPANTS: A total of 344 community-dwelling older adults, aged 70 years and older, who attended a geriatrician-led Falls Prevention Clinic in Vancouver, after sustaining a fall in the previous 12 months. MEASUREMENTS: Main outcome measures included: incidence rate ratio for falls, healthcare costs, incremental cost per fall prevented, and incremental cost per quality-adjusted life year (QALY) gained. RESULTS: The OEP costs $393 CAD per participant to implement. The incremental cost per fall prevented resulted in a savings of $2 CAD. The incremental cost per QALY gained (where QALYs were estimated using the Euro-Qol 5D three-level version [EQ-5D-3L]) indicated the OEP was less effective than usual care. The incremental cost per QALY gained (where QALYs were estimated using the Short Form 6D [SF-6D]) indicated the OEP was more effective and less costly than usual care. The incremental QALYs estimated using the EQ-5D-3L and the SF-6D were not clinically significant and close to zero, indicating no change in quality of life. CONCLUSION: Compared with usual care, healthcare system costs are saved and falls are prevented when older fallers who attend a geriatrician-led falls clinic are allocated to, and provided, the physiotherapist-guided exercise-based falls prevention program (the OEP).

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.

Geriatrician-led evidence-based Falls Prevention Clinic: a prospective 12-month feasibility and acceptability cohort study among older adults.

OBJECTIVE: We assessed the feasibility and acceptability of delivering a geriatrician-led evidence-based Falls Prevention Clinic to older adults with a history of falls. DESIGN: 12-month prospective cohort study. SETTING: Vancouver Falls Prevention Clinic, Vancouver, British Columbia, Canada (www.fallsclinic.ca). PARTICIPANTS: 188 community-dwelling older adults aged ≥70 years who received a baseline assessment at the Vancouver Falls Prevention Clinic due to having had at least one fall resulting in medical attention in the previous 12 months. Fifty-six per cent of participants were also participating in a randomised controlled trial. MEASUREMENTS: Feasibility was ascertained by measuring demand (clinic attendance). Acceptability was measured by compliance with recommendations, completion of monthly fall calendars and patient experience. RESULTS: The attendance was 65% of those eligible and invited. This indicates feasibility for demand. 155 received at least one of the following clinical management recommendations from four domains (compliance reported in %): (1) medication changes (78%); (2) exercise prescription (58%); (3) referrals to other healthcare professionals (78%); and/or (4) lifestyle modifications (35%) excluding exercise. Overall compliance to all recommendations was 69%. Patient experience was related to factors impacting patient perceived physical benefit and attributes influencing patient satisfaction. CONCLUSION: This study demonstrated the feasibility and acceptability of a multifactorial intervention approach based on best available evidence-based medicine.

Western Osteoporosis Alliance Clinical Practice Series: Evaluating the Balance of Benefits and Risks of Long-Term Osteoporosis Therapies.

Osteoporosis is a chronic disease that requires life-long strategies to reduce fracture risk. Few trials have investigated the balance of benefits and risk with long-term use of osteoporosis therapies, and fewer still have investigated the consequences of treatment discontinuation. The best available evidence suggests that up to 10 years of treatment with an oral bisphosphonate maintains the degree of fracture risk reduction observed in the 3-year registration trials. With denosumab, 10 years of therapy appears to provide fracture risk reduction similar to or better than that observed in the 3-year registration trial. Available data suggest an increasing but low risk of fractures with atypical features with increasing duration of bisphosphonate therapy. Published data linking duration of therapy to osteonecrosis of the jaw are lacking for bisphosphonates and denosumab. Other side effects associated with denosumab or bisphosphonates do not appear to be related to therapy duration. The antifracture benefits of long-term therapy with bisphosphonates and denosumab in appropriately selected patients outweigh the low risk of serious side effects.

Slow Processing Speed Predicts Falls in Older Adults With a Falls History: 1-Year Prospective Cohort Study.

BACKGROUND/OBJECTIVES: A previous fall is a strong predictor of future falls. Recent epidemiologic data suggest that deficits in processing speed predict future injurious falls. Our primary objective was to determine a parsimonious predictive model of future falls among older adults who experienced ≥1 fall in the past 12 months based on the following categories: counts of (1) total, (2) indoor, (3) outdoor or (4) non-injurious falls; (5) one mild or severe injury fall (yes vs no); (6) an injurious instead of a non-injurious fall; and (7) an outdoor instead of an indoor fall. DESIGN: 12-month prospective cohort study. SETTING: Vancouver Falls Prevention Clinic, Canada (www.fallsclinic.ca). PARTICIPANTS: Two-hundred and eighty-eight community-dwelling older adults aged ≥70 years with a history of ≥1 fall resulting in medical attention in the previous 12 months. MEASUREMENTS: We employed principal component analysis to reduce the baseline predictor variables to a smaller set of five factors (i.e., processing speed, working memory, emotional functioning, physical functioning and body composition/fall risk profile). Second, we used the extracted five factors as predictors in regression models predicting the incidence of falls over a 12-month prospective observation period. We conducted regression analyses for the seven falls-related categories (defined above). RESULTS: Among older adults with a falls history, processing speed was the most consistent predictor of future falls; poorer processing speed predicted a greater number of total, indoor, outdoor, and non-injurious falls, and a greater likelihood of experiencing at least one mild or severe injurious fall (all P values < .01). CONCLUSION: Poorer performance on the processing speed factor, a trainable factor, was independently associated with the most costly type of falls-injurious falls.

Action seniors! - secondary falls prevention in community-dwelling senior fallers: study protocol for a randomized controlled trial.

BACKGROUND: Falls are a 'geriatric giant' and are the third leading cause of chronic disability worldwide. About 30% of community-dwellers over the age of 65 experience one or more falls every year leading to significant risk for hospitalization, institutionalization, and even death. As the proportion of older adults increases, falls will place an increasing demand and cost on the health care system. Exercise can effectively and efficiently reduce falls. Specifically, the Otago Exercise Program has demonstrated benefit and cost-effectiveness for the primary prevention of falls in four randomized trials of community-dwelling seniors. Although evidence is mounting, few studies have evaluated exercise for secondary falls prevention (that is, preventing falls among those with a significant history of falls). Hence, we propose a randomized controlled trial powered for falls that will, for the first time, assess the efficacy and efficiency of the Otago Exercise Program for secondary falls prevention. METHODS/DESIGN: A randomized controlled trial among 344 community-dwelling seniors aged 70 years and older who attend a falls prevention clinic to assess the efficacy and the cost-effectiveness of a 12-month Otago Exercise Program intervention as a secondary falls prevention strategy. Participants randomized to the control group will continue to behave as they did prior to study enrolment. The economic evaluation will examine the incremental costs and benefits generated by using the Otago Exercise Program intervention versus the control. DISCUSSION: The burden of falls is significant. The challenge is to make a difference - to discover effective, ideally cost-effective, interventions that prevent injurious falls that can be readily translated to the population. Our proposal is very practical - the exercise program requires minimal equipment, the physical therapist expertise is widely available, and seniors in Canada and elsewhere have adopted the program and complied with it. Our innovation includes applying the intervention to a targeted high-risk population, aiming to provide the best value for money. Given society's limited financial resources and the known and increasing burden of falls, there is an urgent need to test this feasible intervention which would be eminently ready for roll out. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: NCT01029171; registered 7 December 2009.

Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday.

The amino-bisphosphonates are first-line therapy for the treatment of most patients with osteoporosis, with proven efficacy to reduce fracture risk at the spine, hip, and other nonvertebral skeletal sites. Further, bisphosphonates have been associated with a significant decrease in morbidity and increase in survival. Following the use of bisphosphonates in millions of patients in clinical practice, some unexpected possible adverse effects have been reported, including osteonecrosis of the jaw, atypical femur fractures, atrial fibrillation, and esophageal cancer. Because bisphosphonates are incorporated into the skeleton and continue to exert an antiresorptive effect for a period of time after dosing is discontinued, the concept of a drug holiday has emerged, whereby the risk of adverse effects might be decreased while the patient still benefits from antifracture efficacy. Patients receiving bisphosphonates who are not at high risk for fracture are potential candidates for a drug holiday, while for those with bone mineral density in the osteoporosis range or previous history of fragility fracture, the benefits of continuing therapy probably far outweigh the risk of harm.

Assessing fracture risk and effects of osteoporosis drugs: bone mineral density and beyond.

Although there have been numerous advances in the assessment of bone strength and fracture risk, the majority of these techniques can only be performed in research laboratories, making them largely unavailable to practicing clinicians. Prospective epidemiologic studies have identified risk factors that can be assessed within the clinic and combined with bone mineral density to allow clinicians to better identify untreated individuals at heightened risk for fracture and to make informed treatment decisions based on 10-year absolute fracture risk. This article discusses the assessment of fracture risk in clinical practice, reviews currently and soon-available bone measurement tools, and details the impacts of osteoporosis therapies on fracture risk.