Vertebral fractures in patients with CKD and the general population: a call for diagnosis and action.

Vertebral fractures (VFs) are the most common osteoporotic fractures in the general population, and they have been associated with high mortality, decreased quality of life, and high risk of subsequent fractures, especially when recent, multiple, or severe. Currently, VF diagnosis and classification determine fracture risk and the most appropriate anti-osteoporotic treatment. However, VFs are clearly underdiagnosed, especially in patients with chronic kidney disease (CKD), and CKD-associated osteoporosis has been disregarded until recently. VFs are associated with higher morbidity and mortality, and their prevalence and incidence differ depending on the grade of renal dysfunction (CKD G1-G5) and/or the type of renal replacement therapy (dialysis or transplantation). In addition to classical risk factors [such as higher age, female sex, reduced bone mineral density, diabetes and steroid use], various other factors have been associated with an increased risk of VFs in CKD, including CKD grade, haemodialysis vintage, time since renal transplantation, low or high intact parathyroid hormone and phosphate levels, and/or vitamin D and K1 deficiencies. Importantly, several clinical societies have recently modified their algorithms according to the fracture risk classification (including the presence of VFs) and determined the most appropriate anti-osteoporotic treatment for the general population. However, there are no specific guidelines addressing this topic in patients with CKD despite an important paradigm shift regarding the prognostic value of bone mineral density in 2017 after the publication of the CKD-Mineral and Bone Disorder Kidney Disease: Improving Global Outcomes guidelines. A proactive attitude towards diagnosis, treatment, and research is proposed to avoid therapeutic nihilism.

Osteoporosis management in patients with chronic kidney disease (ERCOS Study): A challenge in nephrological care.

Fracture risk assessment in patients with chronic kidney disease (CKD) has been included in the CKD-MBD ("Chronic Kidney Disease-Mineral and Bone Disorders") complex in international and national nephrology guidelines, suggesting for the first time the assessment of bone mineral density (BMD) if the results can influence therapeutic decision-making. However, there is very little information on actual clinical practice in this population. The main objective of the ERCOS (ERC-Osteoporosis) study is to describe the profile of patients with CKD G3-5D with osteoporosis (OP) and/or fragility fractures treated in specialized nephrology, rheumatology and internal medicine clinics in Spain. Fifteen centers participated and 162 patients (mostly women [71.2%] postmenopausal [98.3%]) with a median age of 77 years were included. Mean estimated glomerular filtration rate (eGFR) was 36 mL/min/1.73 m2 and 38% of the included patients were on dialysis. We highlight the high frequency of prevalent fragility fractures [37.7%), mainly vertebral (52.5%) and hip (24.6%)], the disproportionate history of patients with glomerular disease compared to purely nephrological series (corticosteroids) and undertreatment for fracture prevention, especially in nephrology consultations. This study is an immediate call to action with the dissemination of the new, more proactive, clinical guidelines, and underlines the need to standardize a coordinated and multidisciplinary care/therapeutic approach to these patients in an efficient way to avoid current discrepancies and therapeutic nihilism.

Evaluating Osteoporosis in Chronic Kidney Disease: Both Bone Quantity and Quality Matter.

Bone strength is determined not only by bone quantity [bone mineral density (BMD)] but also by bone quality, including matrix composition, collagen fiber arrangement, microarchitecture, geometry, mineralization, and bone turnover, among others. These aspects influence elasticity, the load-bearing and repair capacity of bone, and microcrack propagation and are thus key to fractures and their avoidance. In chronic kidney disease (CKD)-associated osteoporosis, factors traditionally associated with a lower bone mass (advanced age or hypogonadism) often coexist with non-traditional factors specific to CKD (uremic toxins or renal osteodystrophy, among others), which will have an impact on bone quality. The gold standard for measuring BMD is dual-energy X-ray absorptiometry, which is widely accepted in the general population and is also capable of predicting fracture risk in CKD. Nevertheless, a significant number of fractures occur in the absence of densitometric World Health Organization (WHO) criteria for osteoporosis, suggesting that methods that also evaluate bone quality need to be considered in order to achieve a comprehensive assessment of fracture risk. The techniques for measuring bone quality are limited by their high cost or invasive nature, which has prevented their implementation in clinical practice. A bone biopsy, high-resolution peripheral quantitative computed tomography, and impact microindentation are some of the methods established to assess bone quality. Herein, we review the current evidence in the literature with the aim of exploring the factors that affect both bone quality and bone quantity in CKD and describing available techniques to assess them.

Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis.

Chronic kidney disease (CKD) is a highly prevalent disease that has become a public health problem. Progression of CKD is associated with serious complications, including the systemic CKD-mineral and bone disorder (CKD-MBD). Laboratory, bone and vascular abnormalities define this condition, and all have been independently related to cardiovascular disease and high mortality rates. The "old" cross-talk between kidney and bone (classically known as "renal osteodystrophies") has been recently expanded to the cardiovascular system, emphasizing the importance of the bone component of CKD-MBD. Moreover, a recently recognized higher susceptibility of patients with CKD to falls and bone fractures led to important paradigm changes in the new CKD-MBD guidelines. Evaluation of bone mineral density and the diagnosis of "osteoporosis" emerges in nephrology as a new possibility "if results will impact clinical decisions". Obviously, it is still reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will be clinically useful (low versus high turnover-bone disease). However, it is now considered that the inability to perform a bone biopsy may not justify withholding antiresorptive therapies to patients with high risk of fracture. This view adds to the effects of parathyroid hormone in CKD patients and the classical treatment of secondary hyperparathyroidism. The availability of new antiosteoporotic treatments bring the opportunity to come back to the basics, and the knowledge of new pathophysiological pathways [OPG/RANKL (LGR4); Wnt-ß-catenin pathway], also affected in CKD, offers great opportunities to further unravel the complex physiopathology of CKD-MBD and to improve outcomes.

Vitamin D and Chronic Kidney Disease Association with Mineral and Bone Disorder: An Appraisal of Tangled Guidelines.

Chronic kidney disease (CKD) is a highly prevalent condition worldwide in which the kidneys lose many abilities, such as the regulation of vitamin D (VD) metabolism. Moreover, people with CKD are at a higher risk of multifactorial VD deficiency, which has been extensively associated with poor outcomes, including bone disease, cardiovascular disease, and higher mortality. Evidence is abundant in terms of the association of negative outcomes with low levels of VD, but recent studies have lowered previous high expectations regarding the beneficial effects of VD supplementation in the general population. Although controversies still exist, the diagnosis and treatment of VD have not been excluded from nephrology guidelines, and much data still supports VD supplementation in CKD patients. In this narrative review, we briefly summarize evolving controversies and useful clinical approaches, underscoring that the adverse effects of VD derivatives must be balanced against the need for effective prevention of progressive and severe secondary hyperparathyroidism. Guidelines vary, but there seems to be general agreement that VD deficiency should be avoided in CKD patients, and it is likely that one should not wait until severe SHPT is present before cautiously starting VD derivatives. Furthermore, it is emphasized that the goal should not be the complete normalization of parathyroid hormone (PTH) levels. New developments may help us to better define optimal VD and PTH at different CKD stages, but large trials are still needed to confirm that VD and precise control of these and other CKD-MBD biomarkers are unequivocally related to improved hard outcomes in this population.

Coexistence of septic and crystal-induced arthritis: A diagnostic challenge. A report of 25 cases. / Coexistencia de artritis séptica y microcristalina: un reto diagnóstico. A propósito de 25 casos.

OBJECTIVE: Septic arthritis is a medical emergency and crystal-induced arthritis is a risk factor for its development. If both occur simultaneously, crystal-induced arthritis may mask the diagnosis of infection and delay antibiotic therapy. METHOD: Retrospective analysis of patients with coexistence of septic and crystal-induced arthritis. We included only patients with isolation of crystals in synovial fluid analysis and positive culture of synovial fluid and/or blood culture. RESULTS: A total of 25 patients (17 men and 8 women) with a mean age of 67 years. The most commonly affected joint was the knee. In synovial fluid cytological studies, the most frequently identified crystals were monosodium urate. Risk factors included diabetes and chronic renal failure. The most frequently isolated germs were methicillin-sensitive S. aureus (48%), methicillin-resistant S. aureus (12%) and Mycobacterium tuberculosis (12%). In all, 36% of subjects required surgical drainage (excluding those caused by M. tuberculosis). Clinical outcome was favorable in 56%, although intercurrent complications were usual (40%). Mortality was 8%. CONCLUSIONS: Coexistence of septic and crystal-induced arthritis represents a diagnostic challenge and requires a high index of suspicion. Gout was the most prevalent crystal-induced arthritis. S. aureus was the most commonly causative pathogen, with a high rate of methicillin-resistant S. aureus infection. If treated early, the outcome is usually favorable, making synovial fluid microbiological study imperative.

Recommendations by the Spanish Society of Rheumatology on Osteoporosis. / Recomendaciones de la Sociedad Española de Reumatología sobre osteoporosis.

OBJECTIVE: To update the recommendations on osteoporosis (OP) of the Spanish Society of Rheumatology (SER) based on the best possible evidence. METHODS: A panel of nine expert rheumatologists in OP was created, previously selected by the SER through an open call. The phases of the work were: identification of the key areas for updating the previous consensus, analysis and synthesis of the scientific evidence (using the SIGN levels of evidence) and formulation of recommendations based on this evidence and consensus techniques. RESULTS: This revision of the recommendations implies an update in the diagnostic evaluation and treatment of OP. It proposes some criteria to consider the high risk of fracture and some indications to start treatment. The recommendations also address issues related to the safety of treatments and the management of special situations such as inflammatory diseases and treatment with glucocorticoids. CONCLUSIONS: We present an update of SER recommendations on OP.

Trends in recombinant protein use in animal production.

Recombinant technologies have made possible the production of a broad catalogue of proteins of interest, including those used for animal production. The most widely studied proteins for the animal sector are those with an important role in reproduction, feed efficiency, and health. Nowadays, mammalian cells and fungi are the preferred choice for recombinant production of hormones for reproductive purposes and fibrolytic enzymes to enhance animal performance, respectively. However, the development of low-cost products is a priority, particularly in livestock. The study of cell factories such as yeast and bacteria has notably increased in the last decades to make the new developed reproductive hormones and fibrolytic enzymes a real alternative to the marketed ones. Important efforts have also been invested to developing new recombinant strategies for prevention and therapy, including passive immunization and modulation of the immune system. This offers the possibility to reduce the use of antibiotics by controlling physiological processes and improve the efficacy of preventing infections. Thus, nowadays different recombinant fibrolytic enzymes, hormones, and therapeutic molecules with optimized properties have been successfully produced through cost-effective processes using microbial cell factories. However, despite the important achievements for reducing protein production expenses, alternative strategies to further reduce these costs are still required. In this context, it is necessary to make a giant leap towards the use of novel strategies, such as nanotechnology, that combined with recombinant technology would make recombinant molecules affordable for animal industry.

Idiopathic Acquired Osteosclerosis in a Middle-Aged Woman With Systemic Lupus Erythematosus.

Widely distributed osteosclerosis is an unusual radiographic finding with multiple causes. A 42-year-old premenopausal Spanish woman gradually acquired dense bone diffusely affecting her axial skeleton and focally affecting her proximal long bones. Systemic lupus erythematosus (SLE) diagnosed in adolescence had been well controlled. She had not fractured or received antiresorptive therapy, and she was hepatitis C virus antibody negative. Family members had low bone mass. Lumbar spine bone mineral density (BMD) measured by dual-photon absorptiometry (DPA) at age 17 years, while receiving glucocorticoids, was 79% the average value of age-matched controls. From ages 30 to 37 years, dual-energy X-ray absorptiometry (DXA) BMD Z-scores steadily increased in her lumbar spine from +3.8 to +7.9, and in her femoral neck from -1.4 to -0.7. Serum calcium and phosphorus levels were consistently normal, 25-hydroxyvitamin D (25OHD) <20 ng/mL, and parathyroid hormone (PTH) sometimes slightly increased. Her reduced estimated glomerular filtration rate (eGFR) was 38 to 55 mL/min. Hypocalciuria likely reflected positive mineral balance. During increasing BMD, turnover markers (serum bone-specific alkaline phosphatase [ALP], procollagen type 1 N propeptide [P1NP], osteocalcin [OCN], and carboxy-terminal cross-linking telopeptide of type 1 collagen [CTx], and urinary amino-terminal cross-linking telopeptide of type 1 collagen [NTx and CTx]) were 1.6- to 2.8-fold above the reference limits. Those of bone formation seemed increased more than those of resorption. FGF-23 was slightly elevated, perhaps from kidney disease. Serum osteoprotegerin (OPG) and TGFß1 levels were normal, but sclerostin (SOST) and receptor activator of nuclear factor kappa-B ligand (RANKL) were elevated. Serum multiplex biomarker profiling confirmed a high level of SOST and RANKL, whereas Dickkopf-1 (DKK-1) seemed low. Matrix metalloproteinases-3 (MMP-3) and -7 (MMP-7) were elevated. Iliac crest biopsy revealed tetracycline labels, no distinction between thick trabeculae and cortical bone, absence of peritrabecular fibrosis, few osteoclasts, and no mastocytosis. Then, for the past 3 years, BMD Z-scores steadily decreased. Skeletal fluorosis, mastocytosis, myelofibrosis, hepatitis C-associated osteosclerosis, multiple myeloma, and aberrant phosphate homeostasis did not explain her osteosclerosis. Mutation analysis of the LRP5, LRP4, SOST, and osteopetrosis genes was negative. Microarray showed no notable copy number variation. Perhaps her osteosclerosis reflected an interval of autoimmune-mediated resistance to SOST and/or RANKL. © 2016 American Society for Bone and Mineral Research.

Sclerostin Expression in Bile Ducts of Patients With Chronic Cholestasis May Influence the Bone Disease in Primary Biliary Cirrhosis.

Sclerostin is involved in the regulation of osteoblastogenesis and little is known about its role in the development of bone disease in primary biliary cirrhosis (PBC), characterized by low bone formation. Therefore, we have assessed the circulating levels and the liver expression of sclerostin in this cholestatic disease. Serum sclerostin levels were measured in 79 women with PBC (mean age 60.6 ± 1.2 years) and in 80 control women. Lumbar and femoral bone mineral density (BMD), as well as parameters of mineral metabolism and bone remodeling, were measured. Moreover, sclerostin gene (SOST) expression in the liver was assessed by real-time PCR in samples of liver tissue taken by biopsy in 11 PBC patients and in 5 normal liver specimens. Presence and distribution of sclerostin was evaluated in liver slices from 11 patients by immunohistochemistry. The severity of histologic lesions was assessed semiquantitatively in the same liver samples. PBC patients had higher sclerostin levels than controls (75.6 ± 3.9 versus 31.7 ± 1.6 pmol/L, p < 0.001). Serum sclerostin correlated inversely with markers of bone formation and resorption. Sclerostin mRNA in the liver was overexpressed compared with control samples (2.7-fold versus healthy liver). Sclerostin was detected by immunohistochemistry in 7 of the 11 liver samples, mainly located in the bile ducts. Liver sclerostin was associated with the severity of cholangitis (p = 0.02) and indirectly with the degree of lobular inflammation (p = 0.03). Sclerostin mRNA expression was higher in samples that tested positive by immunohistochemistry and particularly in those with lobular granuloma (p = 0.02). The increased expression of sclerostin in the liver and the association with histologic cholangitis may explain the high serum levels of this protein in patients with PBC, thus suggesting that sclerostin may influence the decreased bone formation in this cholestatic disease. © 2016 American Society for Bone and Mineral Research.

Effect of recent spinal cord injury on wnt signaling antagonists (sclerostin and dkk-1) and their relationship with bone loss. A 12-month prospective study.

Spinal cord injury (SCI) has been associated with a marked increase in bone loss and bone remodeling, especially short-term after injury. The absence of mechanical load, mediated by osteocyte mechanosensory function, seems to be a causative factor related to bone loss in this condition. However, the pathogenesis and clinical management of this process remain unclear. Therefore, the aim of the study was to analyze the effect of recent SCI on the Wnt pathway antagonists, sclerostin and Dickkopf (Dkk-1), and their relationship with bone turnover and bone mineral density (BMD) evolution. Forty-two patients (aged 35 ± 14yrs) with a recent (<6months) complete SCI were prospectively included. Sclerostin and Dkk-1, bone turnover markers (bone formation: PINP, bone ALP; resorption: sCTx) and BMD (lumbar spine, proximal femur, total body and lower extremities [DXA]) were assessed at baseline and at 6 and 12 months. The results were compared with a healthy control group. 22/42 patients completed the 12-month follow-up. At baseline, SCI patients showed a marked increase in bone markers (PINP and sCTx), remaining significantly increased at up to 6 months of follow-up. Additionally, they presented significantly increased Dkk-1 values throughout the study, whereas sclerostin values did not significantly change. BMD markedly decreased at the proximal femur (-20.2 ± 5.4%, p < 0.01), total body (-5.7 ± 2.2%, p = 0.02) and lower extremities (-13.1 ± 4.5%, p = 0.01) at 12 months. Consequently, 59% of patients developed densitometric osteoporosis at 12 months. Patients with higher Dkk-1 values (>58 pmol/L) at baseline showed higher sublesional BMD loss. In conclusion, this study shows that short-term after SCI there is a marked increase in bone turnover and bone loss, the latter associated with an increase in Dkk-1 serum levels. The persistence of increased levels of this Wnt antagonist throughout the study and their relationship with the magnitude of bone loss suggests a contributory role of this mediator in this process.

[Clinical usefulness of the determination of fibroblast growth factor 23 in the evaluation of patients with osteomalacia]. / Utilidad clínica de la determinación del factor de crecimiento de los fibroblastos 23 en la valoración de pacientes con osteomalacia.

BACKGROUND AND OBJECTIVE: The aim of the present study was to analyze the usefulness of the determination of fibroblast growth factor 23 (FGF23), a regulatory hormone of phosphate metabolism, in the evaluation of patients with osteomalacia of different causes. PATIENTS AND METHOD: Seventeen patients with osteomalacia were included: 12 hypophosphatemic osteomalacia (by several causes), 4 vitamin D-deficiency osteomalacia and one with hypophosphatasia. Plasma C-terminal FGF23 was determined in all patients. RESULTS: FGF23 levels were increased in 6/12 (50%) of patients with hypophosphatemic osteomalacia (2 X-linked, one autosomal dominant, one related HIV therapy and 2 not elucidated). No patient with vitamin D-deficiency osteomalacia or hypophosphatasia presented increased FGF23 levels. CONCLUSION: The determination of FGF23 could be useful in the evaluation of the different types of hypophosphatemic osteomalacia and also in the identification of their associated etiopathogenic mechanisms. Thus, depending on the cause, 50% of the patients with hypophosphatemic osteomalacia showed increased FGF23 values, whereas in vitamin D-deficiency osteomalacia and in hypophosphatasia FGF23 levels were normal.

The role of Wnt signaling and sclerostin in the pathogenesis of glucocorticoid-induced osteoporosis.

Bone formation is suppressed in glucocorticoid-induced osteoporosis. One of the mechanisms by which glucocorticoids depress bone formation is through their effects on the Wnt/ß-catenin signaling pathway, a critical regulator of osteoblastogenesis. Thus, Wnt signaling induces the differentiation of osteoblast precursors toward mature osteoblasts and prevents osteoblast and osteocyte apoptosis. Glucocorticoids increase the expression of Wnt signaling antagonists (sclerostin and Dkk-1) in experimental studies in rodents and cell cultures. However, the scarce data of their effects in humans are somewhat contradictory, probably due to the dose and duration of treatment as well as the characteristics of the patients. A progressive decrease in Dkk-1 serum levels and an increase in circulating sclerostin levels at long-term follow-up have recently been reported in patients treated with high doses of glucocorticoids. This review describes the most recent data on the effects of glucocorticoids on the Wnt signaling pathway, especially on their antagonists, sclerostin and Dkk-1.

Incidence of skeletal fractures after traumatic spinal cord injury: a 10-year follow-up study.

OBJECTIVE: To analyse the incidence and factors related to the development and clinical evolution of fractures in patients with traumatic spinal cord injury. DESIGN: A retrospective 10-year follow-up study. SETTING: Neurorehabilitation centre. SUBJECTS: Sixty-three patients (50M/13F) with a mean age of 36 ± 20 years with recent traumatic spinal cord injury attended over a one-year period (January to December 2000). MAIN MEASURES: Medical reports were reviewed, evaluating risk factors for osteoporosis, fracture incidence during the 10 years following spinal cord injury, severity (ASIA score) and level of spinal cord injury (paraplegia/tetraplegia), type of lesion (spastic/flaccid), weight-bearing standing activity, and the cause, location and evolution of the fracture. RESULTS: Of the 129 patients attending during the study period, 75 had traumatic spinal cord injury (7 died and 5 had no follow-up). Finally, 63 patients were included. Fifty-four per cent had complete motor injury (ASIA A). Twenty-five per cent of these patients developed fractures, with 2.9 fractures per 100 patient-years. The femur was the most frequent location of the fractures. Fractures were observed 6.4 ± 2.4 years after spinal cord injury (range 2-10 years), all in males. Most fractures (70%) were related to low-impact injuries. Fifty per cent presented with associated clinical complications and only 20% of the patients had received anti-osteoporotic treatment. Spinal cord injury severity was the only risk factor for the development of fractures (complete spinal cord injury (ASIA A)) (RR 4.043; 95% confidence interval (CI) 1.081-23.846, P = 0.037). CONCLUSION: The incidence of fractures after spinal cord injury is high, with severity and time since spinal cord injury being the main determinants for their development. Fractures were frequently associated with clinical complications. However, the use of anti-osteoporotic treatment was uncommon.

Bone disease in patients awaiting liver transplantation. Has the situation improved in the last two decades?

In recent years, there has been speculation about the possibility of a reduction in the incidence of fractures after liver transplantation (LT) because of changes in the characteristics of candidates and the use of different immunosuppressive therapies. We analyzed the characteristics of LT candidates (CTC) and compared them with historical data from a group of LT candidate patients (HTC). Data from 60 CTC patients consecutively included in a screening program of metabolic bone disease were compared with data from 60 HTC patients prospectively evaluated between 1992 and 1993. In all patients, we analyzed the clinical and laboratory characteristics, bone mineral density (BMD) dual-energy X-ray absorptiometry, and skeletal fractures. Patients in the CTC group were older than patients in the HTC group. The CTC group had lower femoral neck T scores. No differences were observed between groups in the proportion of patients with osteoporosis (22 vs. 30 %, p = ns) or fractures (36 vs. 33 %, p = ns). The percentage of patients with normal BMD decreased from 38 to 20 %. 25(OH)D values were low in both groups. Only 7.5 % of the CTC patients received calcium and/or vitamin D supplementation. The prevalence of fractures among CTC patients was similar to that seen two decades ago. At present, candidates for LT are older and have lower femoral bone mass. Vitamin D deficiency remains frequent; however, calcium and/or vitamin D supplementation is uncommon.

Randomized trial comparing monthly ibandronate and weekly alendronate for osteoporosis in patients with primary biliary cirrhosis.

UNLABELLED: Osteoporosis resulting in bone fractures is a complication in patients with primary biliary cirrhosis (PBC). Once-weekly alendronate improves bone mass and is well tolerated in these patients, but there is a concern because of poor compliance. Therefore, the efficacy, adherence, and safety of monthly ibandronate (150 mg) with weekly alendronate (70 mg) were compared in a randomized, 2-year study in 42 postmenopausal women with PBC and osteoporosis. Bone mineral density (BMD) of the lumbar spine and proximal femur (by DXA), liver function, and bone markers were measured at entry and every 6 months over 2 years. Adherence to therapy was assessed by the Morisky-Green score. At enrollment, the two groups were similar with respect to age, BMD, severity of cholestasis, previous fractures, and bone markers. Thirty-three patients, 14 in the ibandronate group and 19 in the alendronate group, completed the trial. At 2 years both treatments resulted in a significant increase in BMD at the lumbar spine (from 0.875 ± 0.025 to 0.913 ± 0.026 g/cm(2), P < 0.001 with alendronate, and from 0.898 ± 0.024 to 0.949 ± 0.027 g/cm(2), P < 0.001 with ibandronate). The mean percentage change was 4.5% and 5.7%, respectively (P = not significant). BMD increased at the total hip by 2.0% and 1.2%, respectively. Changes in bone markers were similar in both groups and one patient with alendronate developed a new vertebral fracture. Adherence to therapy was higher with ibandronate (P = 0.009). Neither treatment impaired liver function or cholestasis. CONCLUSION: Both regimens, weekly alendronate and monthly ibandronate, improve bone mass and are comparable in safety for osteoporosis therapy in patients with PBC, although adherence is higher with the monthly regimen. Further larger studies are needed to assess fracture prevention.