Rationale and design of MUSIC OS-EU: an international observational study of the treatment of postmenopausal women for osteoporosis in Europe and Canada.

OBJECTIVES: The Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study (MUSIC OS-EU) was designed to better understand the rate and burden of gastrointestinal (GI) events on clinical and health care outcomes among postmenopausal women with osteoporosis. METHODS: MUSIC OS-EU is a prospective, multinational, observational cohort study of postmenopausal women ≥50 years of age diagnosed with osteoporosis and enrolled in physician clinics in six countries: France, Italy, the Netherlands, Sweden, the United Kingdom, and Canada. The MUSIC OS-EU study has three components: (i) a physician survey to describe their management of osteoporotic patients with GI events; (ii) a retrospective chart survey to describe the receipt and type of osteoporosis medication prescribed; and (iii) a prospective cohort study including untreated and treated patients diagnosed with osteoporosis to investigate the rate of GI events and association with osteoporosis medication use patterns, health-related quality of life, treatment satisfaction and resource utilisation among postmenopausal women with osteoporosis. RESULTS: Physicians at 97 sites completed the physician questionnaire and data for 716 patients were abstracted for the retrospective chart review. Enrolment and the baseline data collection for the prospective cohort study were conducted between March 2012 and June 2013 for 292 untreated and 2,959 treated patients, of whom 684 were new users and 2,275 were experienced users of oral osteoporosis medications. CONCLUSIONS: The results of MUSIC OS-EU will illuminate the association of GI events with the management of osteoporosis and with patient-reported outcomes among postmenopausal women with osteoporosis in Europe and Canada.

Strong relationship between vitamin D status and bone mineral density in anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is associated with impaired bone health and low bone mineral density (BMD) as a consequence of an inadequate peak bone mass in adolescence and bone loss in young adulthood. The vitamin D status with its implications for bone health in patients affected by AN has only been examined previously in small studies. OBJECTIVE: To evaluate the prevalence of vitamin D deficiency and test the hypothesis that patients with AN and vitamin D deficiency might have worse bone metabolism and lower bone density as compared with AN with adequate vitamin D repletion. DESIGN: We analysed the vitamin D status and bone metabolism in a large cohort (n=89) of untreated patients affected by AN, with amenorrhoea. RESULTS: Vitamin D deficiency is widespread in untreated patients with AN: 16.9% had 25OH vitamin D levels below 12 ng/ml, 36% below 20 ng/ml and 58.4% below 30 ng/ml. PTH values were higher and BMD at both femoral sites were lower in patients with vitamin D<20 ng/ml. Progressively higher values of BMD were observed by 4 ranks of 25 OH vitamin D values (severe deficiency: <12 ng/ml, deficiency: ≥12 ng/ml and <20 ng/ml, insufficiency: ≥20 and <30 ng/ml and normal: ≥30 ng/ml). In patients with severe vitamin D deficiency BMD at the hip were significantly lower than that measured in groups with values over 20 ng/ml (p<0.001 for trend). The level of significance did not change for values adjusted for BMI or body weight. CONCLUSION: We found a strong relationship between vitamin D status and hip BMD values with additional benefits for those with 25OHD levels above 20 ng/ml. Our results support the design of a randomized placebo-controlled clinical trial on the effect of vitamin D on BMD in patients with AN. The second point, whether 25OHD should be above 20 or 30 ng/ml remains a discussion point.

Medication use before and after hip fracture: a population-based cohort and case-control study.

BACKGROUND: Osteoporosis, together with age, is the main risk factor for hip fracture, the incidence of which has also been associated with an increased risk of falling or co-morbidities and related pharmacological treatments. OBJECTIVES: The aim of this study was to investigate changes in concomitant pharmacological treatments prescribed before and after hip fracture in elderly patients compared with treatments prescribed to a matched cohort of subjects without hospitalisation for fractures. METHODS: Data relating to the study population were extracted from a large population-based administrative database of the Italian National Health Authorities. A retrospective analysis was conducted involving female patients (6,431) aged ≥65 years and hospitalised for a hip fracture. The control group comprised age-matched subjects (38,586) not hospitalised for fracture. Changes in drug prescriptions 1 year before and 1 year after hip fracture and differences versus controls were compared. RESULTS: Prior to the fracture, patients were taking more anti-Parkinson medications, antidepressants, medications for chronic obstructive pulmonary disease (COPD), bisphosphonates and calcium-vitamin D supplements, although the intake of the routinely monitored drug classes was significantly infrequent. Polypharmacy was less frequent in fractured women before fracture than in controls (22 vs. 25 %, respectively; P < 0.001), but it was more frequent (30 %, P < 0.001) post-fracture. The incidence of fracture was associated with a significant increase in the use of a number of drug classes: insulin, NSAIDs or analgesics, gastroprotectants, loop diuretics, ß-blockers, antidepressants, antiparkinson drugs, antiepileptics and drugs for COPD. CONCLUSION: Our study confirms a strong association between the use of some drugs (antidepressants, antiparkinson drugs, drugs for COPD) and the risk of hip fracture, but drug use is globally less common than in controls. Hip fracture is associated with a significant increase in drug use, suggesting a global deterioration of health conditions.

Dose-dependent short-term effects of single high doses of oral vitamin D(3) on bone turnover markers.

We investigated the short-term effects on bone turnover markers of high doses of vitamin D(3) in order to identify what initial therapeutic dose can be safely administered in vitamin D-deficient subjects. Thirty-seven elderly subjects [mean age 75 ± 3 (SD) years] were consecutively randomized to the administration of a single oral bolus of 600000, 300000, or 100000 IU vitamin D(3). Blood samples were taken at baseline and 1, 3, 7, 14, 30, 60, and 90 days after vitamin D(3) administration. Twenty-four subjects served as controls. No relevant changes in bone turnover markers [C-terminal telopeptides of type I collagen (sCTX) and bone-specific alkaline phosphatase (BAP)] were observed in the controls. In treated patients a dose-dependent effect on sCTX was observed. With the administration of 600,000 IU vitamin D(3) a significant increase of sCTX was observed already at day 1, and it was sustained for 2 months. The changes in sCTX with smaller doses were considerably lower and reached statistical significance only within the first 3 days with the 300,000 IU dose. BAP remained unchanged in patients given 300,000 and 600,000 IU vitamin D(3), while it significantly rose by 15-23 % throughout the observation period in patients given 100,000 IU. Our results indicate that the use of a vitamin D bolus exceeding 100,000 IU may be associated with acute increases of sCTX.

Determinants and effects of vitamin D supplementation on serum 25-hydroxy-vitamin D levels in patients with rheumatoid arthritis.

OBJECTIVES: Osteoporosis (OP) and increased risk of fracture are relevant features in patients with rheumatoid arthritis (RA). Low levels of serum vitamin D are frequently reported and correlate with a higher RA activity. This study evaluated factors related with the prescription of vitamin D supplements in RA patients and variables influencing the achievement of adequate vitamin D levels. METHODS: Study population was made up by 1168 consecutive RA patients from 22 Italian rheumatology centers. Demographic and clinical variables data were collected and 25OH serum vitamin D was measured in all patients. Insufficient serum 25OH vitamin D levels were defined as values lower than 20 ng/mL. RESULTS: The majority of patients (56.0%) was not taking vitamin D supplements. Among the 514 supplemented patients, 196 (38.1%) were taking insufficient dosages (≤440 IU/day). Variables related with the prescription of supplements were older age, female sex, previous bone density assessment and OP diagnosis. Among the 318 patients using daily supplements ≥800 IU, 88 patients (27.7%) did not reach adequate levels of vitamin D. In these patients a higher HAQ score (OR for 1 point=1.62, 95% CI: 1.06-2.49; p=0.03) and poor sun exposure (OR=2.38, 95% CI: 1.05-5.55; p=0.04) were predictors of vitamin D insufficiency. CONCLUSIONS: Vitamin D deficiency is common in patients with RA, even in patients who are regularly using supplements. Vitamin D supplementation is often ineffective even at the recommended dose of 800 IU/day in more disabled patients.

Short-term effects on bone turnover markers of a single high dose of oral vitamin D3.

CONTEXT: Vitamin D deficiency is often treated or prevented by high intermittent doses of vitamin D to achieve a better treatment adherence, but treatment outcomes were contradictory, and even a transient increase in fracture and fall risk was reported. OBJECTIVE: The objective of the study was to investigate the short-term effects on bone turnover markers of a single bolus of vitamin D3. DESIGN, SETTING, PATIENTS, AND INTERVENTION: Twelve elderly subjects (eight women, four men; mean age 76 ± 3 yr) were given a single oral bolus of 600,000 IU vitamin D3. Blood samples were taken at baseline and 1, 3, 7, 14, 30, 60, and 90 d after vitamin D3 administration. Twenty-four subjects served as controls. MAIN OUTCOME MEASURES: Changes in serum levels of 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D, PTH, C-terminal-telopeptides of type I collagen, cross-linked N-telopeptide of type I collagen (sNTX), osteocalcin, and bone-specific alkaline phosphatase. RESULTS: No relevant changes in 25OHD and bone turnover markers were observed in the controls. In treated subjects, serum 25OHD attained a peak increment to 67.1 ± 17.1 ng/ml (P < 0.001) at d 3. Subsequently it slowly decreased to 35.2 ± 5.8 ng/ml (P <0.01 vs. a baseline value of 21.7 ± 5.6 ng/ml). Mean serum PTH concentration decreased by 25-50% and serum 1,25-dihydroxyvitamin D rose by 25-50%. Serum CTX and sNTX rose significantly at d 1 (P < 0.01), they attained a peak increment greater than 50% at d 3, and they subsequently decreased almost back to baseline values at d 90. Serum osteocalcin slightly rose within the first 3 d and then declined by d 60. No changes were observed in serum bone-specific alkaline phosphatase. CONCLUSIONS: Our results indicate that the use of large doses of vitamin D may be associated with acute increases in C-terminal-telopeptides of type I collagen and sNTX, which may explain the negative clinical results obtained by using intermittent high doses of vitamin D to treat or prevent vitamin D deficiency.

Predictors of treatment with osteoporosis medications after recent fragility fractures in a multinational cohort of postmenopausal women.

OBJECTIVES: To determine the proportion of untreated women who reported receiving treatment after incident fracture and to identify factors that predict treatment across an international spectrum of individuals. DESIGN: Prospective observational study. Self-administered questionnaires were mailed at baseline and 1 year. SETTING: Multinational cohort of noninstitutionalized women recruited from 723 primary physician practices in 10 countries. PARTICIPANTS: Sixty thousand three hundred ninety-three postmenopausal women aged 55 and older were recruited with a 2:1 oversampling of women aged 65 and older. MEASUREMENTS: Data collected included participant demographics, medical history, fracture occurrence, medications, and risk factors for fracture. Anti-osteoporosis medications (AOMs) included estrogen, selective estrogen receptor modulators, bisphosphonates, calcitonin, parathyroid hormone, and strontium. RESULTS: After the first year of follow-up, 1,075 women reported an incident fracture. Of these, 17% had started AOM, including 15% of those with a single fracture and 35% with multiple fractures. Predictors of treatment included baseline calcium use (P = .01), baseline diagnosis of osteoporosis (P < .001), and fracture type (P < .001). In multivariable analysis, women taking calcium supplements at baseline (odds ratio (OR) = 1.67) and with a baseline diagnosis of osteoporosis (OR = 2.55) were more likely to be taking AOM. Hip fracture (OR = 2.61), spine fracture (OR = 6.61), and multiple fractures (OR = 3.79) were associated with AOM treatment. Age, global region, and use of high-risk medications were not associated with treatment. CONCLUSION: More than 80% of older women with new fractures were not treated, despite the availability of AOM. Important factors associated with treatment in this international cohort included diagnosis of osteoporosis before the incident fracture, spine fracture, and to a lesser degree, hip fracture.

Densitometric threshold and vertebral fractures in heart transplant patients.

BACKGROUND: Bone disease is one of the major complications of solid organ transplantation, causes considerable morbidity, and most patients are treated with immunosuppressant drugs after graft. The majority of studies reported rapid bone loss and an increased incidence of fractures after transplantation. The aim of our study was to evaluate osteoporosis and fracture prevalence, bone metabolism, and the effect of immunosuppressant agents on bone after heart transplantation. METHODS: We planned a cross-sectional study in 180 heart transplant patients recruited from 3 different centers with a less than 10 years from graft. Each patient underwent a densitometric scan, and in 157 of them, an x-ray of the spine was performed to evaluate fractures. Biochemical assessment of bone metabolism was made at the time of the visit. Physical activity, diet, and calcium intake were evaluated using a specific questionnaire. RESULTS: Vertebral fractures were diagnosed in 40% of subjects, but densitometric osteoporosis was observed only in 13% of spine and in 25% of hip scans. Interestingly, increasing T-score threshold up to -1.5 standard deviation, the prevalence of fractured patient improved significantly, reaching 60% in both genders. Bone content was inversely correlated with glucocorticoids, while a positive correlation was found with cyclosporine A. Almost all subjects had vitamin D deficiency. CONCLUSIONS: Standard densitometric criteria are unreliable to identify bone fragility after transplantation, and a different threshold (-1.5 standard deviation) should be considered. Transplanted patients should be adequately supplemented with vitamin D, and the effects of immunosuppressant agents on bone need further investigation.

Relationship of focal erosions, bone mineral density, and parathyroid hormone in rheumatoid arthritis.

OBJECTIVE: To investigate the relationship among focal bone erosions and bone mineral density (BMD), 25(OH) vitamin D (25OHD), and parathyroid hormone (PTH) values in patients with rheumatoid arthritis (RA). METHODS: The study included 1191 RA patients (1014 women, 177 men, mean age 58.9 ± 11.1 yrs) participating in a multicenter, cross-sectional study. RESULTS: Radiographic evidence of typical bony erosions on hands or forefeet was found in 64.1% of patients. In those with bone erosions as compared to those without, mean BMD Z score values were significantly lower at both the spine (-0.74 ± 1.19 vs -0.46 ± 1.31; p = 0.05) and the hip (-0.72 ± 1.07 vs -0.15 ± 1.23; p < 0.001). In the subgroup of patients not taking vitamin D supplements, PTH levels were significantly higher in those with erosive arthritis (25.9 ± 14.0 vs 23.1 ± 11.6 pg/ml; p = 0.01); whereas the 25OHD concentrations were very similar in the 2 groups. The mean differences for BMD and PTH among the erosive and nonerosive RA remained statistically significant when values were simultaneously adjusted for all disease and mineral metabolism factors (i.e., age, sex, menopause, disease duration, Disease Activity Score 28-joint count, Health Assessment Questionnaire, activities of daily living, Steinbrocker functional state, glucocorticoid therapy, body weight, and bisphosphonate treatment). CONCLUSION: Our results suggest that the presence of bone erosions in RA correlates with low BMD levels and high PTH levels, and that these associations are independent of the degree of functional impairment and other common determinants of bone mass and mineral metabolism in adults with RA. These findings suggest that treatments to prevent bone loss or suppress PTH levels might positively affect the progression of bone erosions in RA.

Vitamin D deficiency in rheumatoid arthritis: prevalence, determinants and associations with disease activity and disability.

INTRODUCTION: The aim of this study was to estimate the prevalence and determinants of vitamin D deficiency in patients with rheumatoid arthritis (RA) as compared to healthy controls and to analyze the association between 25-hydroxyvitamin D (25(OH)D) with disease activity and disability. METHODS: The study includes 1,191 consecutive RA patients (85% women) and 1,019 controls, not on vitamin D supplements, from 22 Italian rheumatology centres. Together with parameters of disease activity, functional impairment, and mean sun exposure time, all patients had serum 25(OH)D measured in a centralized laboratory. RESULTS: A total of 55% of RA patients were not taking vitamin D supplements; the proportion of these with vitamin D deficiency (25(OH)D level <20 ng/ml) was 52%. This proportion was similar to that observed in control subjects (58.7%). One third of supplemented patients were still vitamin D deficient. In non-supplemented RA patients 25(OH)D levels were negatively correlated with the Health Assessment Questionnaire Disability Index, Disease Activity Score (DAS28), and Mobility Activities of daily living score. Significantly lower 25(OH)D values were found in patients not in disease remission or responding poorly to treatment, and with the highest Steinbrocker functional state. Body mass index (BMI) and sun exposure time were good predictors of 25(OH)D values (P < 0.001). The association between disease activity or functional scores and 25(OH)D levels remained statistically significant even after adjusting 25(OH)D levels for both BMI and sun exposure time. CONCLUSIONS: In RA patients vitamin D deficiency is quite common, but similar to that found in control subjects; disease activity and disability scores are inversely related to 25(OH)D levels.

Capacitively coupled electric field for pain relief in patients with vertebral fractures and chronic pain.

UNLABELLED: Fragility vertebral fractures often are associated with chronic back pain controlled by analgesic compounds. Capacitive coupling electrical stimulation is a type of electrical stimulation technology approved by the US FDA to noninvasively enhance fracture repair and spinal fusion. These uses suggest it would be a possible treatment for patients with back pain attributable to vertebral fractures. We therefore randomized 51 postmenopausal women with multiple fractures and chronic pain to the use of one of two indistinguishable devices delivering either the standard capacitive coupling electrical stimulation by Osteospine (active group) or low intensity pulse (control group). Twenty patients of the active group and 21 of the control group (80%) completed the study for a total duration of 3 months. The mean visual analog scale values for pain and the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) scores improved in both groups. We observed a relationship between hours of treatments and reductions in pain intensity only in the active group. Capacitive coupling electrical stimulation was not more effective than control treatment when comparing mean visual analog scale pain and QALEFFO scores in the two groups and when adjusting for the hours of treatment. However, the proportion of patients able to discontinue NSAIDs owing to elimination or reduction of pain was greater in the active group than in the control group. We interpret these findings as suggesting capacitive coupling electrical stimulation controls pain in some patients and reduces the use of NSAIDs. LEVEL OF EVIDENCE: Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Neridronic acid for the treatment of bone metabolic diseases.

Neridronic acid (6-amino-1-idroxyesilidene-1,1-bisphosphonate) is a nitrogen-containing bisphosphonate licensed in Italy for the treatment of osteogenesis imperfecta and Paget's disease of bone. The pharmacodynamic profile is similar to that of other nitrogen-containing bisphosphonates and is characterized by its high affinity for bone tissue particularly at sites undergoing a process of remodeling. In growing children affected by osteogenesis imperfect, neridronic acid rapidly increases bone mineral density as measured by dual X-ray absortiometry and this is associated with a significant decrease in fracture cumulative number. Similar results have been obtained also in newborns (< 12 month old) and in adult patients. In Paget's disease of bone, 200 mg intravenous neridronic acid is associated with a 65% rate of full remission and a biochemical response (decrease of > 75% of bone turnover markers) in 95% of the patients. Neridronic acid treatment has been reported to be effective also in other skeletal diseases such as osteoporosis, algodystrophy, hypercalcemia of malignancy and bone metastasis. Neridronic acid has been developed only for parenteral use, and it is the only one used as intramuscular injection. This avoids all the limitations of oral bisphosphonates and may be offered for a home treatment with simple nursing assistance.

Intramuscular neridronate in postmenopausal women with low bone mineral density.

Compliance to osteoporosis treatment with oral bisphosphonates is very poor. Intermittent intravenous bisphosphonate is a useful alternative, but this route is not readily available. Neridronate, a nitrogen-containing bisphosphonate that can be given intramuscularly (IM), was tested in a phase 2 clinical trial in 188 postmenopausal osteoporotic women randomized to IM treatment with 25 mg neridronate every 2 weeks, neridronate 12.5 or 25 mg every 4 weeks, or placebo. All patients received calcium and vitamin D supplements. The patients were treated over 12 months with 2-year posttreatment follow-up. After 12-month treatment, all three doses were associated with significant bone mineral density (BMD) increases at both the total hip and spine. A significant dose-response relationship over the three doses was observed for the BMD changes at the total hip but not at the spine. Bone alkaline phosphatase decreased significantly by 40-55% in neridronate-treated patients, with an insignificant dose-response relationship. Serum type I collagen C-telopeptide decreased by 58-79%, with a significant dose-response relationship (P < 0.05). Two years after treatment discontinuation, BMD declined by 1-2% in each dose group, with values still significantly higher than baseline at both the spine and the total hip. Bone turnover markers progressively increased after treatment discontinuation, and on the second year of follow-up the values were significantly higher than pretreatment baseline. The results of this study indicate that IM neridronate might be of value for patients intolerant to oral bisphosphonates and unwilling or unable to undergo intravenous infusion of bisphosphonates.

Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study.

OBJECTIVE: An effective and well tolerated intravenous (IV) bisphosphonate could provide a new treatment method for patients with osteoporosis. The Dosing IntraVenous Administration (DIVA) study was designed to identify the optimal ibandronate IV injection schedule for the treatment of postmenopausal osteoporosis by comparing the efficacy and tolerability of 2- and 3-monthly injections with the previously evaluated daily oral ibandronate regimen. We report the effects on lumbar spine and proximal femur bone mineral density (BMD) and bone resorption markers over 2 years. METHODS: This randomized, double-blind, double-dummy, noninferiority study recruited 1395 women (aged 55-80 yrs; > or = 5 yrs since menopause) with osteoporosis [mean lumbar spine (L2-L4) BMD T-score < -2.5 and > or = -5.0]. Patients received IV ibandronate (2 mg every 2 mo or 3 mg every 3 mo) plus daily oral placebo, or 2.5 mg daily oral ibandronate plus 2- or 3-monthly IV placebo. Supplemental vitamin D (400 IU) and calcium (500 mg) were provided throughout the 2-year study. RESULTS: At 2 years, the 2- and 3-monthly IV regimens achieved statistically noninferior and also superior increases in lumbar spine BMD compared with the daily regimen (6.4% and 6.3% vs 4.8%, respectively; p < 0.001). Greater increases were also obtained with IV ibandronate versus daily in proximal femur BMD. Serum concentrations of the biochemical marker of bone resorption C-telopeptide of the alpha-chain of type I collagen were reduced to a similar extent in all treatment arms (53.4%-59.9%). The tolerability profile of the IV regimens was similar to that observed with daily oral therapy. CONCLUSION: Ibandronate IV injections are an effective and well tolerated treatment for postmenopausal osteoporosis and provide a useful alternative to oral dosing.

Relationship between serum parathyroid hormone, vitamin D sufficiency, age, and calcium intake.

Vitamin D deficiency is extremely common among elderly subjects and it has been associated with poor bone health, and to a number of other conditions. The ideal 25-hydroxy-vitamin D [25(OH)D] concentration, reflecting the size of vitamin D deposits, are generally retained those not associated with any marginal increase in serum parathyroid hormone (PTH). These threshold values vary considerably and this may be due to the interaction of other factors. The aim of the study is to assess whether age and calcium intake interact with the relationship between 25(OH)D and PTH. Data from a survey on the prevalence of hypovitaminosis D in elderly women in Italy were analysed in order to verify whether age and calcium intake were interfering on the 25(OH)D/PTH relationship. A total of 697 women were available for analysis. Serum PTH levels were significantly correlated with age, 25(OH)D and calcium intake (p<0.001) and in a multivariate model they all significantly contributed to explain PTH variance (R(2)=24.4%). In 39 elderly osteoporotic women on a low calcium intake and given vitamin D supplements (2000-3000 IU daily for >8 months) able to increase 25(OH)D levels above 110 nMol/l, PTH levels were maintained below 35 pg/mL. The minimum 25(OH)D levels to be recommended depends largely on the age and the calcium intake. In elderly individuals not taking calcium supplements in order to keep serum PTH levels strictly within the normal range 25(OH)D serum levels should be maintained above ca. 120 nMol/L.

Fracture incidence and characterization in patients on osteoporosis treatment: the ICARO study.

UNLABELLED: None of the available osteoporosis therapies have been shown to completely abolish the risk of fractures. In clinical practice, the outcome may be even poorer. In 880 patients prescribed with antiresorptives (alendronate, risedronate, and raloxifene) for >1 year, a fragility fracture was recorded in 8.9%/year of them. This incidence is considerably higher than that observed in randomized clinical trials, and it was significantly related to poor compliance and lack of supplementation with calcium and vitamin D. INTRODUCTION: Osteoporotic fracture is one of the most important public health concerns among the elderly. Currently available therapies have been shown to significantly decrease the risk of fracture, although none of them completely abolishes this risk. In clinical practice, poor treatment response may also result from a number of other factors. MATERIALS AND METHODS: The Incidence and ChAracterization of inadequate clinical Responders in Osteoporosis (ICARO) is a multicenter, observational study carried out in Italy. It aimed to analyze, in postmenopausal women with established osteoporosis, the risk factors for an "inadequate clinical response" to drug therapy, defined as the occurrence of new vertebral or nonvertebral fragility fractures in patients prescribed, for at least 1 year, alendronate, risedronate, or raloxifene, with a compliance >50%. RESULTS: In 880 patients treated with antiresorptive agents for a median of 2.0 years (95% CI: 1.0-4.5) years, the "inadequate clinical responder (ICR)" subjects over the observation period were 220 (25%), with an annual incidence of 8.9%. ICRs, compared with "adequate clinical responders (ACRs)," had more pretreatment fractures and were treated longer (2.8 versus 1.8 years; p < 0.001). After multiple adjustment for these confounding factors, significant determinants of inadequate clinical response were a poorer treatment compliance and a less frequent co-administration of calcium and vitamin D supplements. CONCLUSIONS: The incidence of fractures during treatment with antiresorptive agents in a clinical setting is considerably higher than that observed in randomized clinical trials. Inadequate compliance to treatment and lack of supplementation of calcium and vitamin D are major determinants of this poor response.

Effect of oral vitamin D2 yearly bolus on hip fracture risk in elderly women: a community primary prevention study.

BACKGROUND AND AIMS: Vitamin D deficiency is a well-known risk for hip fracture, and vitamin D insufficiency is so frequent in the elderly that population-wide preventive intervention would be useful. The objective of the study was to evaluate the efficacy of vitamin D bolus on hip fracture incidence in elderly women. METHODS: All women aged > 65 years registered at Health District 20 of the Regione Veneto, Italy, were eligible for this quasi-experimental, prospective community intervention study. A vial containing 400,000 IU vitamin D2 (Ostelin 800, Teofarma, Italy) was offered for oral administration to all women in the winters of 2000-2001 and 2001-2002. The only exclusion criteria for treatment were age and gender, and the control group included women who did not participate in the Health District initiative. Analysis of hip fracture incidence was carried out for 4 years, from 1999 to 2002. Patients with incident hip fracture were identified as soon as they were admitted to one of the 3 hospitals of the health district and interviewed regarding their participation in the vitamin D preventive intervention program. In 120 of the women (age range 68-90 years), serum concentrations of 25-OH vitamin D were measured from October to June, both before and 1 and 4 months after vitamin D administration. RESULTS: 23,325 and 24,747 women received the vitamin D bolus during winters 2000-2001 and 2001-2002 respectively, i.e. 45-47% of eligible women. The proportion of women who accepted the bolus declined with advancing age, from 50-55% in women aged 60-70 years to 22-26% in those aged > 90 years. The two-year intervention on the community decreased the incidence of fracture by 10% (p = 0.050) in comparison with the previous two years. The age-adjusted risk reduction (RR) of hip fracture during 2001 and 2002 in women who had received vitamin D, with respect to women who had not, decreased by 17% (p = 0.056) and 25% (p = 0.005) respectively. The RR was considerably greater and statistically significant over both 2001 and 2002 in the cohort aged > 75 years. 25-OH vitamin D concentrations, in the subset of women in whom it was measured, rose significantly (p < 0.0001) by 9 ng/ml over 4 months after administration. CONCLUSION: Despite several obvious limitations due to its nature, this study sufficiently documents that yearly vitamin D bolus supplements, given as primary prevention to elderly Caucasian women, may decrease the incidence of hip fracture. For its probable safety and excellent feasibility and cost-effectiveness, this primary intervention has a great potential for generalisability.