Romosozumab: confusión respecto a sus indicaciones / Romosozumab: confusion regarding its indications

El romosozumab es, sin duda, un excelente fármaco para el tratamiento de la osteoporosis. No obstante, su elevadoprecio, muy superior al de los fármacos antirresortivos, hizo que inicialmente se aceptara sin dificultad que su indicaciónse limitase a pacientes con un riesgo de fractura particularmente elevado. Sin embargo, la aplicación de esta idea en lapráctica se ha encontrado con algunos problemas. En primer lugar, para describir tal indicación se han utilizado términosdistintos (“riesgo muy alto”, “riesgo alto”, “osteoporosis grave”), el significado concreto de cada uno de los cuales,además, es diferente para unos y otros autores. Por otra parte, y sin un fundamento científico suficiente, se han idointroduciendo conceptos que pretenden ampliar las indicaciones del fármaco hasta prácticamente proponer la genera-lización de su uso (“riesgo inminente”, comienzo del tratamiento de la osteoporosis con anabólicos de forma universalo cuasi-universal). Todo ello ha generado confusión en el médico prescriptor, y ha dado lugar a que las autoridadessanitarias hayan impuesto para su uso normas que han resultado demasiado restrictivas. En el artículo se desarrollanestas ideas -y algunas otras- con detalle.(AU)

Long-Term Treatment and Effect of Discontinuation of Calcifediol in Postmenopausal Women with Vitamin D Deficiency: A Randomized Trial.

Vitamin D plays a major role in bone health and probably also in multiple extraskeletal acute and chronic diseases. Although supplementation with calcifediol, a vitamin D metabolite, has demonstrated efficacy and safety in short-term clinical trials, its effects after long-term monthly administration have been studied less extensively. This report describes the results of a 1-year, phase III-IV, double-blind, randomized, controlled, parallel, multicenter superiority clinical trial to assess the efficacy and safety of monthly calcifediol 0.266 mg versus cholecalciferol 25,000 IU (0.625 mg) in postmenopausal women with vitamin D deficiency (25(OH)D < 20 ng/mL). A total of 303 women were randomized and 298 evaluated. Patients were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months (Group A1), calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months (Group A2), and cholecalciferol 25,000 IU/month (0.625 mg/month) for 12 months (Group B). By month 4, stable 25(OH)D levels were documented with both calcifediol and cholecalciferol (intention-to-treat population): 26.8 ± 8.5 ng/mL (Group A1) and 23.1 ± 5.4 ng/mL (Group B). By month 12, 25(OH)D levels were 23.9 ± 8.0 ng/mL (Group A1) and 22.4 ± 5.5 ng/mL (Group B). When calcifediol treatment was withdrawn in Group A2, 25(OH)D levels decreased to baseline levels (28.5 ± 8.7 ng/mL at month 4 versus 14.4 ± 6.0 ng/mL at month 12). No relevant treatment-related safety issues were reported in any of the groups. The results confirm that long-term treatment with monthly calcifediol in vitamin D-deficient patients is effective and safe. The withdrawal of treatment leads to a pronounced decrease of 25(OH)D levels. Calcifediol presented a faster onset of action compared to monthly cholecalciferol. Long-term treatment produces stable and sustained 25(OH)D concentrations with no associated safety concerns. © 2023 Faes Farma SA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Aminobisfosfonatos: reconsideración a los 25 años de su aprobación para el tratamiento de la osteoporosis / Aminobisphosphonates: Reconsideration 25 years after their approval for the treatment of osteoporosis

Aminobisphosphonates are widely used in the treatment of osteoporosis. They have a high affinity for hydroxyapatite, binding primarily to resorbing surfaces, but also to forming surfaces and to some extent to resting surfaces. They inhibit osteoclasts, thereby decreasing remodelling units. Consequently, they increase bone mass and reduce stress risers. This decreases the risk of fractures. If this decrease is sufficient, they can be temporarily withdrawn (drug holidays), which prevents serious complications (atypical femoral fracture). They probably reduce mortality. Virtually all patients with osteoporosis can benefit from them at some point in the course of their disease (at the beginning of treatment or after the administration of anabolics, selective estrogen receptor modulators or denosumab). If well tolerated orally, alendronate and risedronate are preferable. Otherwise, zoledronate is preferred. Their efficacy vs. cost-safety-convenience ratio makes aminobisphosphonates reference drugs in the field of osteoporosis. (AU)

Los aminobisfosfonatos se utilizan ampliamente en el tratamiento de la osteoporosis. Tienen gran afinidad por la hidroxiapatita, uniéndose fundamentalmente a las superficies en resorción, pero también a las superficies en formación y, en cierta medida, a las superficies en reposo. Inhiben a los osteoclastos, con lo que disminuyen las unidades de remodelación. En consecuencia, aumentan la masa ósea y reducen los concentradores de tensión. Ello disminuye el riesgo de fracturas. Si esta disminución es suficiente, pueden retirarse transitoriamente (vacaciones terapéuticas), lo que previene complicaciones graves (fractura atípica de fémur). Probablemente disminuyen la mortalidad. Pueden beneficiarse de ellos prácticamente todos los enfermos con osteoporosis en algún momento de su evolución (al comienzo del tratamiento o tras la administración de anabólicos, moduladores selectivos de los receptores estrogénicos o denosumab). Con buena tolerancia oral son preferibles el alendronato y el risedronato. En caso contrario, lo es el zoledronato. Su relación eficacia frente a coste-seguridad-comodidad los convierte en fármacos de referencia en el campo de la osteoporosis. (AU)

Sarcopenic osteoporosis, sarcopenic obesity, and sarcopenic osteoporotic obesity in the Camargo cohort (Cantabria, Spain).

The associations of sarcopenia with osteoporosis or obesity have a very low prevalence. No trend towards an association between osteoporosis and sarcopenia is observed. Sarcopenia and obesity tend not to coincide, as if they were antagonistic disorders. PURPOSE: To know (a) the prevalence in our region of sarcopenic osteoporosis (association of sarcopenia and osteoporosis (T-score < - 2.5)), sarcopenic obesity, and the association of osteoporosis, sarcopenia, and obesity; (b) the tendency of osteoporosis, sarcopenia, and obesity to associate with each other; and (c) the bone mineral density (BMD), the components of sarcopenia, and the prevalence of fragility fractures in these associations. METHODS: The study was performed in the Camargo cohort. Osteoporosis was diagnosed by DXA, sarcopenia by the EWGSOP-1 criteria, and obesity by body mass index (BMI) and fat percentage. Fractures were verified radiographically or by consulting the medical records. RESULTS: The prevalence of sarcopenic osteoporosis was 2.8% and the OR for this association 1.03 (p = 0.89). The prevalence of sarcopenic obesity by BMI was 1.4% and by fat percentage 5.9% (corresponding ORs: 0.18 (p < 0.0001) and 0.58 (p < 0.003) respectively). The prevalence of the association of osteoporosis, sarcopenia, and obesity was 0.0% when assessed by BMI and 0.8% when assessed by fat percentage. Patients with sarcopenic osteoporosis have less muscle mass and more fragility fractures than sarcopenic patients overall. In patients with sarcopenic obesity by fat percentage, muscle mass and strength, as well as physical performance, were similar to those of sarcopenic patients overall. Neither BMD nor fracture prevalence showed differences between patients with sarcopenic obesity and patients with sarcopenia or obesity in general. CONCLUSION: Our study supports the idea that the prevalence of the mixed disorders studied is low. No significant association between osteoporosis and sarcopenia was found. Sarcopenia and obesity seem to tend to occur in different people, as if suffering from one of them hinders suffering from the other.

Aminobisphosphonates: Reconsideration 25 years after their approval for the treatment of osteoporosis. / Aminobisfosfonatos: reconsideración a los 25 años de su aprobación para el tratamiento de la osteoporosis.

Aminobisphosphonates are widely used in the treatment of osteoporosis. They have a high affinity for hydroxyapatite, binding primarily to resorbing surfaces, but also to forming surfaces and to some extent to resting surfaces. They inhibit osteoclasts, thereby decreasing remodelling units. Consequently, they increase bone mass and reduce stress risers. This decreases the risk of fractures. If this decrease is sufficient, they can be temporarily withdrawn (drug holidays), which prevents serious complications (atypical femoral fracture). They probably reduce mortality. Virtually all patients with osteoporosis can benefit from them at some point in the course of their disease (at the beginning of treatment or after the administration of anabolics, selective estrogen receptor modulators or denosumab). If well tolerated orally, alendronate and risedronate are preferable. Otherwise, zoledronate is preferred. Their efficacy vs. cost-safety-convenience ratio makes aminobisphosphonates reference drugs in the field of osteoporosis.

Calcifediol is superior to cholecalciferol in improving vitamin D status in postmenopausal women: a randomized trial.

Vitamin D has shown to play a role in multiple diseases due to its skeletal and extraskeletal actions. Furthermore, vitamin D deficiency has become a worldwide health issue. Few supplementation guidelines mention calcifediol treatment, despite being the direct precursor of calcitriol and the biomarker of vitamin D status. This 1-year, phase III-IV, double-blind, randomized, controlled, multicenter clinical trial assessed the efficacy and safety of calcifediol 0.266 mg soft capsules in vitamin D-deficient postmenopausal women, compared to cholecalciferol. Results reported here are from a prespecified interim analysis, for the evaluation of the study's primary endpoint: the percentage of patients with serum 25-hydroxyvitamin D (25(OH)D) levels above 30 ng/ml after 4 months. A total of 303 patients were enrolled, of whom 298 were included in the intention-to-treat (ITT) population. Patients with baseline levels of serum 25(OH)D <20 ng/ml were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months, calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months, and cholecalciferol 25,000 IU/month for 12 months. At month 4, 35.0% of postmenopausal women treated with calcifediol and 8.2% of those treated with cholecalciferol reached serum 25(OH)D levels above 30 ng/ml (p < 0.0001). The most remarkable difference between both drugs in terms of mean change in serum 25(OH)D levels was observed after the first month of treatment (mean ± standard deviation change = 9.7 ± 6.7 and 5.1 ± 3.5 ng/ml in patients treated with calcifediol and cholecalciferol, respectively). No relevant treatment-related safety issues were reported in any of the groups studied. These results thus confirm that calcifediol is effective, faster, and more potent than cholecalciferol in raising serum 25(OH)D levels and is a valuable option for the treatment of vitamin D deficiency. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

COVID-19 y fractura por fragilidad de la cadera. Recomendaciones conjuntas de la Sociedad Española de Fracturas Osteoporóticas y la Sociedad Española de Geriatría y Gerontología / COVID-19 and fragility hip fracture. Joint recommendations of the Spanish Society of Osteoporotic Fractures and the Spanish Society of Geriatrics and Gerontology

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Bone mineral density and trabecular bone score in treatment-naïve patients with non-cirrhotic hepatitis C virus infection.

We studied 112 treatment-naïve chronic HCV patients without cirrhosis, and we found that, especially HCV+ postmenopausal women, they had lower TBS and BMD values than healthy controls. This suggests that HCV infection is an independent risk factor for osteoporosis, and therefore, screening for osteoporosis in postmenopausal HCV+ women should be considered. PURPOSE: To know whether patients in earlier stages of chronic HCV infection are at increased risk of developing low bone mass and bone microarchitectural changes and whether there is an association between bone metabolism and the severity of the liver disease. METHODS: We studied 112 treatment-naïve chronic HCV outpatients and 233 healthy age- and sex-matched controls. Bone mineral density (BMD) and trabecular bone score (TBS) were assessed by DXA. Serum 25(OH)D, PTH, P1NP, and CTX were determined by electrochemiluminescence. RESULTS: TBS values were significantly lower in HCV patients than in controls, both considering the population as a whole (1.337 ± 0.119 vs. 1.377 ± 0.122; p < 0.005) and after stratifying by sex (1.347 ± 0.12 vs. 1.381 ± 0.13 in men and 1.314 ± 0.10 vs. 1.369 ± 0.11 in women). The difference remained significant (p < 0.0001 in all cases) after adjusting for confounders. BMD was also lower in HCV patients (lumbar spine, 0.935 ± 0.151 vs. 0.991 ± 0.143 g/cm2, p 0.001; femoral neck, 0.764 ± 0.123 vs. 0.818 ± 0.123 g/cm2, p 0.0001; total hip, 0.926 ± 0.148 vs. 0.963 ± 0.132 g/cm2, p 0.02), although, after adjustment, differences kept a clear trend towards statistical significance in women at the lumbar spine and femoral neck. However, in men and at the total hip in women, differences were no longer significant. We find no relationship between these parameters and the severity of the disease. No significant difference was observed in PTH and 25OHD status after adjustment. Finally, serum P1NP, but not CTX, was higher in HCV patients. CONCLUSIONS: Our findings suggest that HCV infection is an independent risk factor for osteoporosis, especially among postmenopausal women. Therefore, the appropriateness of screening for osteoporosis in postmenopausal HCV-positive women should be considered.

Trabecular bone score and bone quantitative ultrasound in Spanish postmenopausal women. The Camargo Cohort Study.

OBJECTIVE: To evaluate trabecular bone score (TBS) in Spanish postmenopausal women from our area. To analyze its relationship with bone mineral density (BMD), bone quantitative ultrasound (QUS) and serum concentrations of 25-hydroxyvitamin D (25(OH)D), intact parathyroid hormone (PTH) and bone turnover markers. STUDY DESIGN: A total of 1450 postmenopausal women aged 44-94 (62 ± 10) participated in this cross-sectional study nested in a population-based cohort. BMD and TBS were assessed by DXA. QUS measurements were performed using a Sahara Clinical Sonometer. Serum 25(OH)D, PTH, P1NP, ß-CTX were determined by electrochemiluminescence. RESULTS: Mean TBS of postmenopausal women in our region was 1.341 ± 0.111. Nearly 50 % of them had normal values. Only 11 % had scores compatible with a clearly degraded microarchitecture. TBS decreased with age, correlated negatively with BMI and was lower in current smokers than in non-smokers. An association was observed between TBS and QUS, although the association was weak and lower than that found between TBS and BMD or QUS and BMD. No association was found between TBS and 25(OH)D, PTH or bone turnover markers. CONCLUSIONS: Half of postmenopausal women in our region have TBS values that indicate a preserved microarchitecture. Only about 10 % have scores compatible with a clearly degraded microarchitecture. A weak association was observed between TBS and QUS, suggesting that the two techniques capture different aspects of bone microarchitecture. The absence of association with 25(OH)D, PTH, and bone turnover markers may be due to the fact that TBS assesses a specific (mostly trabecular) part of the skeleton, whilst the three serum factors are related to the whole skeleton.

In-hospital care, complications, and 4-month mortality following a hip or proximal femur fracture: the Spanish registry of osteoporotic femur fractures prospective cohort study.

We have characterised 997 hip fracture patients from a representative 45 Spanish hospitals, and followed them up prospectively for up to 4 months. Despite suboptimal surgical delays (average 59.1 hours), in-hospital mortality was lower than in Northern European cohorts. The secondary fracture prevention gap is unacceptably high at 85%. PURPOSE: To characterise inpatient care, complications, and 4-month mortality following a hip or proximal femur fracture in Spain. METHODS: Design: prospective cohort study. Consecutive sample of patients ≥ 50 years old admitted in a representative 45 hospitals for a hip or proximal femur fragility fracture, from June 2014 to June 2016 and followed up for 4 months post-fracture. Patient characteristics, site of fracture, in-patient care (including secondary fracture prevention) and complications, and 4-month mortality are described. RESULTS: A total of 997 subjects (765 women) of mean (standard deviation) age 83.6 (8.4) years were included. Previous history of fracture/s (36.9%) and falls (43%) were common, and 10-year FRAX-estimated major and hip fracture risks were 15.2% (9.0%) and 8.5% (7.6%) respectively. Inter-trochanteric (44.6%) and displaced intra-capsular (28.0%) were the most common fracture sites, and fixation with short intramedullary nail (38.6%) with spinal anaesthesia (75.5%) the most common procedures. Surgery and rehabilitation were initiated within a mean 59.1 (56.7) and 61.9 (55.1) hours respectively, and average length of stay was 11.5 (9.3) days. Antithrombotic and antibiotic prophylaxis were given to 99.8% and 98.2% respectively, whilst only 12.4% received secondary fracture prevention at discharge. Common complications included delirium (36.1 %) and kidney failure (14.1%), with in-hospital and 4-month mortality of 2.1% and 11% respectively. CONCLUSIONS: Despite suboptimal surgical delay, post-hip fracture mortality is low in Spanish hospitals. The secondary fracture prevention gap is unacceptably high at > 85%, in spite of virtually universal anti-thrombotic and antibiotic prophylaxis.

Serum 25-Hydroxyvitamin D in Obese Spanish Adults: the Camargo Cohort Study.

OBJECTIVES: To describe the 25(OH)D status in Spanish obese postmenopausal women and men ≥ 50 years, to compare their results with those of the overweight or normal weight population, and to determine whether differences are observed between both sexes and with seasonal variation throughout the year. PATIENTS AND METHODS: We studied 2597 subjects (1826 postmenopausal women and 771 men ≥ 50 years). Serum concentrations of 25(OH)D, intact parathyroid hormone (PTH), aminoterminal propeptide of type I collagen (PINP), and C-terminal telopeptide of type I collagen (CTX) were determined by electrochemiluminiscence (Elecsys 2010, Roche). Bone mineral density (BMD) was measured by DXA. Participants were divided according to body mass index (BMI) groups (normal ≥ 20 and < 25 kg/m2, overweight ≥ 25 and < 30 kg/m2, or obese ≥ 30 kg/m2). RESULTS: Obese people had lower serum 25(OH)D values (20.9 ± 8.2 ng/ml) than overweight (23.3 ± 8.8 ng/ml; p < 0.0001) or normal-weight subjects (24.4 ± 8.9 ng/ml; p < 0.0001). They have also lower levels of both PINP and CTX. In contrast, PTH concentrations and BDM values were higher in obese individuals. When stratifying by sex, the difference in serum concentration of 25(OH)D remained significant in women, but not in men, persisted throughout the year, and was inversely correlated with BMI and waist circumference. CONCLUSIONS: Despite lower serum 25(OH)D concentrations and higher PTH levels, obese and overweight women have higher lumbar spine and hip BMD and lower bone remodeling markers than normal weight women, suggesting that low serum 25(OH)D levels do not negatively affect bone health.

Prevalence of vertebral fracture and densitometric osteoporosis in Spanish adult men: The Camargo Cohort Study.

The aim of this study was to assess the prevalence of densitometric osteoporosis and vertebral fractures in Spanish men aged ≥50 years, and to study how the relationship between them may change depending on how osteoporosis is diagnosed. A community-based population of 1003 men aged ≥50 years was studied. Bone mineral density (BMD) was measured by DXA at the lumbar spine, femoral neck and total hip. Vertebral fractures were assessed by lateral thoracic and lumbar spine radiographs. The prevalence of osteoporosis was estimated with both the World Health Organization (WHO) (T-score of <-2.5 at the femoral neck, calculated using the young white female normal reference database) and the National Osteoporosis Foundation (NOF) criteria (T-score of <-2.5 at the femoral neck, total hip or lumbar spine, calculated using the young white male normal reference database). The prevalence of osteoporosis using the WHO criterion was 1.1% and using the NOF criterion was 13%, while that of vertebral fractures was 21.3%. The area under the curve (AUC) for the relationship between BMD and vertebral fracture prevalence was 0.64. The odds ratio for osteoporosis using the WHO definition was 2.57 (p = 0.13), and 1.78 (p = 0.007) using the NOF definition. Vertebral fracture prevalence rose with age. The prevalence of osteoporosis increased only moderately in men aged >70 years with the WHO criterion, and showed no change using the NOF definition. The prevalence of osteoporosis in Spanish men using the WHO definition is too small to have any meaningful clinical use. Although the figure is higher using the NOF definition, it would seem that population-based studies of BMD in men are of questionable value.

SNPs in bone-related miRNAs are associated with the osteoporotic phenotype.

Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.

Relationship between spinal osteoarthritis and vertebral fractures in men older than 50 years: data from the Camargo Cohort Study.

Spinal osteoarthritis has been suggested as a risk factor for vertebral fractures. However, results are conflicting: most of the data are focused on the lumbar region, and referred to postmenopausal women, whereas data for men are scarce. The aim of this study is to assess the relationship between spinal osteoarthritis and vertebral fractures in men over 50 years of age. We conducted a cross-sectional study, nested in a prospective population-based cohort, including 507 community-dwelling men, 93 of them with at least one vertebral fracture. Vertebral fractures, osteophytosis, and disc space narrowing (DSN) were assessed by lateral thoracic and lumbar radiographs. Anthropometric, clinical, and densitometric variables were also analyzed. A multiple logistic regression model was performed. Eighty-five percent of vertebral fractures were located at the thoracic spine. Osteophytosis and DSN showed a bimodal distribution, with major frequency peaks at mid- and distal lumbar spine. The three distributions overlapped around the T9 vertebra. We did not find any relationship between lumbar osteoarthritis and vertebral fractures. Nevertheless, thoracic osteophytosis (OR, 1.84; 95 % CI, 1.05-3.17; p = 0.03) and DSN (OR, 2.52; 95 % CI, 1.43-4.46; p = 0.001) were found to be independently associated with prevalent vertebral fractures, after adjusting for confounders. Our results suggest a positive relationship between radiologic osteoarthritic changes at the thoracic spine and prevalent vertebral fractures in men more than 50 years of age. Osteoarthritis may act as a local risk factor, in addition to other mechanical factors, resulting in a greater propensity to fracture, especially at the mid-thoracic region.

CathepsinKCre mediated deletion of ßcatenin results in dramatic loss of bone mass by targeting both osteoclasts and osteoblastic cells.

It is well established that activation of Wnt/ßcatenin signaling in the osteoblast lineage leads to an increase in bone mass through a dual mechanism: increased osteoblastogenesis and decreased osteoclastogenesis. However, the effect of this pathway on the osteoclast lineage has been less explored. Here, we aimed to examine the effects of Wnt/ßcatenin signaling in mature osteoclasts by generating mice lacking ßcatenin in CathepsinK-expressing cells (Ctnnb1f/f;CtsKCre mice). These mice developed a severe low-bone-mass phenotype with onset in the second month and in correlation with an excessive number of osteoclasts, detected by TRAP staining and histomorphometric quantification. We found that WNT3A, through the canonical pathway, promoted osteoclast apoptosis and therefore attenuated the number of M-CSF and RANKL-derived osteoclasts in vitro. This reveals a cell-autonomous effect of Wnt/ßcatenin signaling in controlling the life span of mature osteoclasts. Furthermore, bone Opg expression in Ctnnb1f/f;CtsKCre mice was dramatically decreased pointing to an additional external activation of osteoclasts. Accordingly, expression of CathepsinK was detected in TRAP-negative cells of the inner periosteal layer also expressing Col1. Our results indicate that the bone phenotype of Ctnnb1f/f;CtsKCre animals combines a cell-autonomous effect in the mature osteoclast with indirect effects due to the additional targeting of osteoblastic cells.

Circulating sclerostin and estradiol levels are associated with inadequate response to bisphosphonates in postmenopausal women with osteoporosis.

INTRODUCTION: The biological mechanisms associated with an inadequate response to treatment with bisphosphonates are not well known. This study investigates the association between circulating levels of sclerostin and estradiol with an inadequate clinical outcome to bisphosphonate therapy in women with postmenopausal osteoporosis. METHODS: This case-control study is based on 120 Spanish women with postmenopausal osteoporosis being treated with oral bisphosphonates. Patients were classified as adequate responders (ARs, n=66, mean age 68.2±8 years) without incident fractures during 5 years of treatment, or inadequate responders (IRs, n=54, mean age 67±9 years), with incident fractures between 1 and 5 years of treatment. Bone mineral density (DXA), structural analysis of the proximal femur and structural/fractal analysis of the distal radius were assessed. Sclerostin concentrations were measured by ELISA and 17ß-estradiol levels by radioimmunoassay based on ultrasensitive methods. RESULTS: In the ARs group, sclerostin serum levels were significantly lower (p=0.02) and estradiol concentrations significantly higher (p=0.023) than in the IRs group. A logistic regression analysis was performed, including as independent variables in the original model femoral fracture load, 25 hydroxyvitamin D, previus history of fragility fracture, sclerostin and estradiol. Only previous history of fragility fracture (OR 14.04, 95% CI 2.38-82.79, p=0.004) and sclerostin levels (OR 1.11, 95% CI 1.02-1.20, p=0.011), both adjusted by estradiol levels remained associated with IRs. Also, sclerostin concentrations were associated with the index of resistance to compression (IRC) in the fractal analysis of the distal radius, a parameter on bone microstructure. CONCLUSIONS: Sclerostin and estradiol levels are associated with the response to bisphosphonate therapy in women with postmenopausal osteoporosis.

Influence of vitamin D status on the effect of statins on bone mineral density and bone turnover markers in postmenopausal women.

OBJECTIVE: This study sought to assess whether the association between statin use and bone mineral density (BMD) and bone turnover markers is modulated by serum 25-hydroxyvitamin D (25OHD) levels in postmenopausal women. Design, Participants, and Settings: Approximately 1422 postmenopausal women were recruited from the Camargo Cohort after excluding those with any known medical disorder or drug that might affect bone metabolism. Participants were categorized into four groups: 25OHD levels of 20 ng/mL or less and not taking statins (group 1; n = 492); 25OHD levels greater than 20 ng/mL and on statins (group 2; n = 143); 25OHD levels of 20 ng/mL or less and using statins (group 3; n = 112); and 2OHD levels greater than 20 ng/mL and non-statin use (group 4; n = 675). Multivariate analyses were performed to compare BMD and bone turnover markers between groups. RESULTS: Women in group 2 had an adjusted femoral neck and total hip BMD higher than women in group 1 (P < .0001 and P = .003, respectively). A trend toward a significant difference was observed regarding lumbar BMD (P = .08). Serum aminoterminal propeptide of type 1 collagen and C-terminal telopeptide of type 1 collagen levels were lower in group 2 than in group 1, in crude and adjusted models, although only serum C-terminal telopeptide of type 1 collagen difference was significant (P = .009). CONCLUSIONS: Women on statins and serum 25OHD levels above 20 ng/mL have greater BMD and less bone resorption than those without either of the factors. Differences, however, are not significant in women with only one of them. Vitamin D and statins seem to interact positively in their effects on bone metabolism.

Bone mineral density in statin users: a population-based analysis from a Spanish cohort.

We studied 2,315 subjects (1,422 women and 893 men) from the Camargo Cohort and analyzed the differences in BMD between statin or non-statin users. We also studied effects of the type of statin, dose, pharmacokinetic properties, and length of treatment on bone mineral density (BMD). Of the subjects, 478 (21 %) were taking statins (256 women and 222 men). Overall, they had higher BMD than non-users (p < 0.0001). In adjusted multivariate models, women taking statins had higher BMD at femoral neck (p = 0.002) and total hip (p = 0.04) than non- users. No differences were found in men. Women taking simvastatin had higher increases in BMD than non-statin users at femoral neck (p = 0.02) and total hip (p = 0.009), those taking fluvastatin had lower BMD values at lumbar spine (p = 0.028), and those receiving lovastatin had higher increases at femoral neck (p = 0.006). In men, only atorvastatin was associated with higher femoral neck BMD than non-statin use (p = 0.029). Comparing with non-statin users, only women receiving lipophilic statins had greater BMD at femoral neck (p = 0.003). According to drug potency, women on high- or lower-potency agents showed higher BMD values at femoral neck than non-users (p = 0.028 and 0.022, respectively). In men, only high-potency statins were associated with higher femoral neck BMD than non-use (p = 0.021). No differences between dose or length of statin therapy were noted regarding BMD in either sex. In summary, in a large population-based cohort, women on statins had higher BMD at the hip than non-users. Overall, this increase in BMD was more evident in subjects on lipophilic or high-potency statins.