Guidelines for the diagnosis, prevention and management of osteoporosis.

Osteoporosis poses a significant public health issue. National Societies have developed Guidelines for the diagnosis and treatment of this disorder with an effort of adapting specific tools for risk assessment on the peculiar characteristics of a given population. The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has recently revised the previously published Guidelines on the diagnosis, riskassessment, prevention and management of primary and secondary osteoporosis. The guidelines were first drafted by a working group and then approved by the board of SIOMMMS. Subsequently they received also the endorsement of other major Scientific Societies that deal with bone metabolic disease. These recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on leading experts' experience and opinion, and on good clinical practice. The osteoporosis prevention should be based on the elimination of specific risk factors. The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk, and this is the case only when the risk of fracture is rather high as measured with variables susceptible to pharmacological effect. DeFRA (FRAX® derived fracture risk assessment) is recognized as a useful tool for easily estimate the long-term fracture risk. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management.

Treatment with intermittent PTH increases Wnt10b production by T cells in osteoporotic patients.

UNLABELLED: We evaluated the effect of parathyroid hormone (PTH) on Wnt10b production by immune system cells in humans. We showed that bone anabolic effect of intermittent PTH treatment may be amplified by T cells through increased production of Wnt10b. Chronic increase in PTH as in primary hyperparathyroidism does not increase Wnt10b expression. INTRODUCTION: The aim of this study is to assess the effect of PTH on Wnt10b production by immune system cells in humans. We assessed both the effect of intermittent PTH administration (iPTH) and of chronic PTH hypersecretion in primary hyperparathyroidism (PHP). METHODS: Eighty-two women affected by post-menopausal osteoporosis were randomly assigned to treatment with calcium and vitamin D alone (22) or plus 1-84 PTH (42), or intravenous ibandronate (18). Wnt10b production by unfractioned blood nucleated cells and by T, B cells and monocytes was assessed by real-time RT-PCR and ELISA at baseline, 3, 6, 12 and 18 months of treatment. The effect of chronic elevation of PTH was evaluated in 20 patients affected by PHP at diagnosis and after surgical removal of parathyroid adenoma. WNT10b from both osteoporotic and PHP patients was compared to healthy subjects matched for age and sex. RESULTS: iPTH increases Wnt10b production by T cells, whereas PHP does not. After surgical restoration of normal parathyroid function, WNT10b decreases, although it is still comparable with healthy subjects' level. Thus, chronic elevation of PTH does not significantly increase WNT10b production as respect to control. CONCLUSIONS: This is the first work showing the effect of both intermittent and chronic PTH increase on Wnt10b production by immune system cells. We suggest that, in humans, T cells amplified the anabolic effect of PTH on bone, by increasing Wnt10b production, which stimulates osteoblast activity.

Teriparatide increases the maturation of circulating osteoblast precursors.

UNLABELLED: This study shows that teriparatide promotes the circulating osteoblast (OB) precursor degree of maturation in patients affected by postmenopausal osteoporosis. INTRODUCTION: Anabolic treatment with teriparatide has proven effective for the therapy of postmenopausal osteoporosis and significantly reduces the risk of non-vertebral fragility fractures. The aim of this study was to investigate the effect of teriparatide on circulating OB precursors. METHODS: We evaluated by flow cytometry and real-time PCR the expression of OBs typical markers in peripheral blood mononuclear cells during treatment with teriparatide plus calcium and vitamin D, raloxifene plus calcium and vitamin D or calcium and vitamin D alone at various time points. Serum bone alkaline phosphatase and osteocalcin (OC) were measured as markers of bone turnover. RESULTS: Our results show that circulating OB precursors are more numerous and more immature in patients affected by fragility fractures than in osteoporotic patients without fractures. We also show that teriparatide treatment increases the expression of alkaline phosphatase and of OC in OB precursors; thus, it increases their degree of maturation. CONCLUSIONS: We suggest that teriparatide acts as anabolic agents also by promoting the maturation of OB precursors.

Clinical characteristics and incidence of first fracture in a consecutive sample of post-menopausal women attending osteoporosis centers: The PROTEO-1 study.

BACKGROUND: Osteoporosis is a highly prevalent disease and fractures are a major cause of disability and morbidity. AIM: The purpose of this study was to characterize post-menopausal women attending osteoporosis centers in Italy, to evaluate physician management, and to determine the incidence of first osteoporotic fracture. SUBJECTS AND METHODS: PROTEO-1 was an observational longitudinal study with a 12-month follow-up. Data were collected from women attending osteoporosis centers. Women without prevalent fracture were eligible to enter the 1-yr follow-up phase: the clinical approach to patients according to their fracture risk profile and the incidence of fracture were recorded. RESULTS: 4269 patients were enrolled in 80 centers in the cross-sectional phase; 34.2% had an osteoporotic fracture at baseline. Patients with prevalent fractures were older and more likely to be treated compared with non-fractured patients. The incidence of vertebral or hip fracture after 1 yr was 3.84%, regardless of the calculated risk factor profile, and was significantly higher in patients with back pain at baseline (4.2%) compared with those without back pain (2.2%; p=0.023). Generally, physicians prescribed more blood exams and drugs to patients at higher risk of fracture. Among fractured patients only 24% were properly treated; the rate of non-responders to treatment was about 4%. CONCLUSIONS: In a large, unselected sample of post-menopausal women attending osteoporosis centers, those without previous fracture were at substantial risk of future fracture, regardless of their theoretical low 10-yr fracture risk. The presence of back pain in women without previous fracture warrants close attention.

Bone and bone marrow pro-osteoclastogenic cytokines are up-regulated in osteoporosis fragility fractures.

UNLABELLED: This study evaluates cytokines production in bone and bone marrow of patients with an osteoporotic fracture or with osteoarthritis by real time PCR, Western blot and immunohistochemistry. We demonstrate that the cytokine pattern is shifted towards osteoclast activation and osteoblast inhibition in patients with osteoporotic fractures. INTRODUCTION: Fragility fractures are the resultant of low bone mass and poor bone architecture typical of osteoporosis. Cytokines involved in the control of bone cell maturation and function are produced by both bone itself and bone marrow cells, but the roles of these two sources in its control and the amounts they produce are not clear. This study compares their production in patients with an osteoporotic fracture and those with osteoarthritis. METHODS: We evaluated 52 femoral heads from women subjected to hip-joint replacement surgery for femoral neck fractures due to low-energy trauma (37), or for osteoarthritis (15). Total RNA was extracted from both bone and bone marrow, and quantitative PCR was used to identify the receptor activator of nuclear factor kB Ligand (RANKL), osteoprotegerin (OPG), macrophage colony stimulating factor (M-CSF), transforming growth factor ß (TGFß), Dickoppf-1 (DKK-1) and sclerostin (SOST) expression. Immunohistochemistry and Western blot were performed in order to quantify and localize in bone and bone marrow the cytokines. RESULTS: We found an increase of RANKL/OPG ratio, M-CSF, SOST and DKK-1 in fractured patients, whereas TGFß was increased in osteoarthritic bone. Bone marrow produced greater amounts of RANKL, M-CSF and TGFß compared to bone, whereas the production of DKK-1 and SOST was higher in bone. CONCLUSIONS: We show that bone marrow cells produced the greater amount of pro-osteoclastogenic cytokines, whereas bone cells produced higher amount of osteoblast inhibitors in patients with fragility fracture, thus the cytokine pattern is shifted towards osteoclast activation and osteoblast inhibition in these patients.

Alendronate reduces osteoclast precursors in osteoporosis.

UNLABELLED: This study evaluates the effect of alendronate on osteoclastogenesis, cytokine production, and bone resorption in postmenopausal women. We suggest that it acts on mature bone resorbing osteoclasts after 3 months of treatment, whereas, after 1 year, it diminishes their formation by reducing their precursors and serum RANKL. INTRODUCTION: Osteoclasts are the target cells of bisphosphonates, though the most drug-sensitive steps of their formation and activity have not been determined. The present study evaluates the effect of alendronate on osteoclastogenesis, cytokine production, and bone resorption in postmenopausal women. METHODS: The study was conducted on 35 osteoporotic women; 15 were pretreated with alendronate 70 mg/week, whereas, 20 were treated with calcium 1 g/day and vitamin D 800 IU/day. After 3 months, 30 received alendonate 70/mg, vitamin D 2800 IU/week, and calcium 1 g/day for 12 months (combined therapy), whereas, the other five patients remained on calcium 1 g/day and vitamin D 800 IU/day. The following parameters were assessed before and after therapy: changes in bone resorption markers, circulating osteoclast precursors, formation of osteoclasts in peripheral blood mononuclear cell cultures, their viability, and variations in cytokines production. RESULTS: After 3 months of alendronate, there was no significant reduction in the number of osteoclast precursors, osteoclast formation and viability, and cytokine levels, whereas, there was a significant reduction of bone resorption markers. One year of the combined therapy, on the other hand, reduced osteoclast precursors, osteoclast formation, and serum RANKL, whereas, calcium plus vitamin D alone had no effect. CONCLUSIONS: We suggest that alendronate mainly acts on mature bone resorbing osteoclasts in the short term, whereas, its long-term administration diminishes their formation by reducing their precursors and serum RANKL.

The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease.

Osteoporosis and atherosclerosis are degenerative disorders of old age that often present together, but recently it has been suggested that the association between osteoporosis and cardio-vascular diseases is not just due to the aging process. The osteoprotegerin (OPG)/receptor activator of nuclear factor-kB (RANK)/RANK ligand (RANKL) system has been identified as a possible mediator of arterial calcification suggesting common links between osteoporosis and vascular diseases. Since the discovery of the OPG/RANK/RANKL system, much has been learned about its role in controlling skeletal biology; however, its role in the context of vascular biology is only beginning to be explored. It has been suggested that OPG might act as an autocrine/paracrine regulator of vascular calcification and might be useful as a serum marker of vascular disease. However, the exact role of OPG (or RANKL/RANK) in vascular calcification is still not completely understood. This review aims to report the recent findings on the relationship between osteoporosis and OPG/RANK/RANKL-mediated vascular disease.

[Guidelines for the diagnosis, prevention and treatment of osteoporosis]. / Linee guida per la diagnosi, prevenzione e terapia dell'osteoporosi Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro - SIOMMMS.

UNLABELLED: The guidelines for the osteoporosis management were first drafted by a working group and then critically evaluated by the board of SIOMMMS. The most relevant points are: DEFINITION: Osteoporosis is defined as a quantitative and qualitative deterioration of bone tissue leading to increased risk of fracture. Postmenopausal and senile osteoporosis are defined as primitive. DIAGNOSIS: The cornerstone for the diagnosis of osteoporosis is the measurement of bone mineral density (BMD) by DXA (dual-energy X-ray absortiometry) at the femoral neck with T-score values <-2.5, following the WHO definition. Other DXA sites or technologies for measuring bone mass are also acceptable when the former is not accessible. A BMD evaluation is recommended to all women above 65 years of age. At younger age or in man the bone assessment is recommended only in subjects with specific risk factors. A control of bone mass measurement is seldom required before 2 years. DIFFERENTIAL DIAGNOSIS: A few biochemical tests such as serum and urinary calcium, protein electrophoresis, serum creatinine and ESR are usually sufficient to exclude most secondary types of osteoporosis. The value of the so called bone turnover markers for the diagnosis and follow-up of osteoporosis remains uncertain. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management. PREVENTION: The osteoporosis prevention should be based on the elimination of specific risk factors such as inadequate calcium and vitamin D intake, smoking and sedentary life. The use of pharmacological agents in subjects with BMD values >-2.5 is usually not justified. Pharmacological intervention: The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk. This is the case only when the risk of fracture is rather high. FRAX is recognized as a useful tool for easily estimate the long-term fracture risk. SIOMMMS with these guidelines is committed to validate and further develop this diagnostic tool.

[Fractures and chronic renal insufficiency]. / La patologia fratturativa nei diversi gradi di insufficienza renale cronica.

Chronic renal insufficiency (CRI) causes important modifications in the metabolism of phosphorus and calcium, to which frequently resulting in serious disorders of the skeleton, including demineralization, reduction of the bone resistance and a higher risk of fractures. Renal osteodystrophy is the term used to describe these disorders; they are generally heterogeneous and are classified according to the state of bone turnover into secondary hyperparathyroidism, adynamic bone, and osteomalacia. The incidence of hip fractures in the patients with CRI is higher than in the general population. Hip fractures are an important cause of morbidity and mortality. The evaluation of the fracture risk in the patients with different degrees of CRI is problematic, in particular because of the difficulty in identifying fractures, especially vertebral ones. The instrumental index that best expresses the fracture risk in the general population is bone mineral density (BMD); however, the relationship between low BMD and CRI is disputed. Bone disorders in patients with CRI have in fact a multifactorial pathogenesis and low BMD is not the only risk factor for fractures. Besides densitometric evaluation, also that vertebral morphometric evaluation would be desirable in patients with CRI. The fracture risk increases progressively with the severity of chronic renal disease and it is especially high in patients with renal insufficiency in more advanced-stages CRI (creatinine clearance<15-20 mL/min). However, not only in patients with severe CRI undergoing dialysis, but also in those with milder renal disease is the risk of bone fractures high.

Acute adrenal crisis and hypercalcemia in a patient assuming high liquorice doses.

Two months after monolateral adrenalectomy, a 47-year-old woman stopped taking corticosteroid replacement therapy in the first 15 days of therapy. She was admitted to the Department of Internal Medicine because of hypertension, severe hypercalcemia, uncompensated metabolic alkalosis and clinical symptoms of acute adrenal insufficiency. The presence of hypokalemia and hypernatremia precluded a diagnosis of hypocortisolism, therefore no corticosteroids were given during the time required to investigate the cause of hypercalcemia, which resulted negative. Administration of intravenous saline infusion produced no improvement in her clinical condition. Despite electrolyte alterations, hydrocortison (100 mg i.v.) and zoledronate (4 mg i.v.) were also administered, leading to a rapid and marked improvement in her clinical picture within a few hours, with normalization of the calcemia and the other electrolytic disturbances. After her neurological condition had fully normalized, the patient admitted she had been assuming large amounts of liquorice as a laxative for many years; this compound very likely compensated the adrenal insufficiency by inhibiting 11 b steroid-dehydrogenase and disguised the clinical presentation at the time of admission. This case report confirms that, though rare, hypercalcemia may be a finding in acute adrenal insufficiency and can be rapidly corrected by corticosteroid administration. Furthermore, excessive liquorice intake can induce a clinical picture resembling that of primary hyperaldosteronism. In patients with adrenal insufficiency, it can, at least in part, disguise its metabolic effects and delay diagnosis and treatment.

[Italian guidelines for the diagnosis and treatment of Paget's disease of bone]. / Linee guida per la diagnosi e la terapia del morbo di Paget.

Paget's disease of bone is a chronic focal abnormality of bone turnover that remains totally asymptomatic over a very long period of time but that eventually ensue in bone pain and skeletal deformities. Although, in the last decade new insights have been obtained on its etiology, this remains largely obscure. Effective medical treatment (based on the use of bisphosphonates) has become available and the diagnostic procedures are now well defined. However, there remains considerable controversy regarding the hierarchy of diagnostic procedures and the medical treatment threshold. In the last few years different institution have published national guidelines, reflecting local national health systems and the available medical treatment. In this review, a working group derived from members of the SIOMMMS has examined the information available regarding the diagnosis and treatment of Paget's disease in order to develop guidelines to assist in the management of this condition. The first draft was then extensively reviewed by experts derived from the most representative scientific societies of rheumatology, internal medicine, and orthopaedic surgery. The document provides the most updated recommendations based primarily on the "evidence-based- medicine" but also on the Italian regulation for the diagnostic procedures and on the available medical treatments.

Superiority of alfacalcidol compared to vitamin D plus calcium in lumbar bone mineral density in postmenopausal osteoporosis.

In a randomized multicenter, double-blind, double-dummy, parallel group study a comparison of the efficacy and safety of 1 microg alfacalcidol to 880 IU vitamin D plus calcium carbonate (1 g calcium) once daily per os was performed on 148 postmenopausal osteoporotic Caucasian patients with normal vitamin D serum levels for 18 months. Bone mineral density (BMD) was measured at baseline, 12 and 18 months. Safety parameters were followed during the entire study period. Sixty-nine (90.8%) in the alfacalcidol group and 67 (93.1%) in the vitamin D group were included in the ITT analysis. Lumbar BMD in the alfacalcidol group increased by 0.017 g/cm2 (2.33%) and 0.021 g/cm2 (2.87%) from baseline (P<0.001) at 12 and 18 months, respectively, whereas in the vitamin D plus calcium group the increase was 0.005 g/cm2 (0.70%) from baseline (N.S.) at both 12 and 18 months. The higher changes from baseline in the alfacalcidol group, as compared to the changes in the vitamin D plus calcium group at both 12 and 18 months, were found to be statistically significant (P=0.018, 0.005). A small increase of mean femoral BMD was achieved in both groups (N.S.). Adverse events were similar in both groups. No significant differences were noted between the groups in serum calcium. In conclusion, alfacalcidol was found to be superior in significantly increasing lumbar BMD as compared to vitamin D plus calcium while safety characteristics were found to be similar in both treatments.

Is leptin the link between fat and bone mass?

Leptin is a cytokine-like hormone which is considered the link between fat and bone; it is produced by adipocytes and osteoblasts, regulates food intake via specific receptors located in the central nervous system (CNS) and bone mass through alternate pathways: one involving a direct stimulatory effect on bone formation; and another indirect effect through the CNS that suppresses bone formation. Leptin exerts a direct stimulatory effect on osteoblast differentiation and on bone growth if directly administered, while it exerts an inhibitory effect on bone formation if administered in the CNS. It is therefore unclear whether leptin should be considered an antiosteogenic factor or an anabolic agent for bone formation: in all probability, leptin has a broader role in human physiology and in particular its action has evolved in order to synchronize periods of bone growth, mineral accretion and fertility with periods of food availability, while it restricts growth and reproduction during periods of nutritional stress.

Role of TNF-alpha producing T-cells in bone loss induced by estrogen deficiency.

Many study in literature have suggested a possible role of T cells and tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of bone loss that occurs in pathological conditions, such as systemic inflammatory diseases; the molecular bases through which this phenomenon occurs and the relevance of this mechanism also in estrogen deficiency induced bone loss remain unclear. In our study we observed that TNF-alpha knock-out mice (TNF-/-), as well as transgenic mice without thymus (and therefore without mature T cell), do not lose bone after ovariectomy like observed for mice of normal genetic background (wild type, WT). Moreover, after transfer into athymic mice of T cell isolated from WT ovariectomized animals (and so stimulated by estrogen deficiency to proliferate and to produce TNF-alpha), ovariectomy recovers its ability to induce bone loss; whereas there is no change in bone density after injection into athymic mice of T-cell purified from TNF-/- animals which, even if mature, are unable to produce TNF-alpha. Therefore the presence of TNF-alpha producing T-cell is essential for estrogen deficiency to influence bone metabolism. In the following study of the research group of Prof. Pacifici it has been shown that the increased activation of TNF-alpha producing T-cell in the ovariectomized mice is due to increased INF-gamma levels, resulting from ovariectomy-induced enhanced secretion of IL-12 and IL-18 by macrophages. INF-gamma promotes expression in immunocompetent cells of class II transactivator (CIITA), that, up-regulating expression of the major system of histocompatibility of class II, makes the macrophages more active in antigen presentation to T-cells, which in turn start producing TNF. For the first time an immune mechanism is involved in the pathogenesis of post-menopausal osteoporosis; nevertheless the applicability of these conclusions also in humans remains still to be proved.

Effect of age, weight and lifestyle factors on calcaneal quantitative ultrasound in premenopausal women: the ESOPO study.

The objective of this study was to identify the determinants of bone mass as measured by quantitative ultrasound (QUS) in premenopausal women. The study population is part of the "Epidemiological Study On the Prevalence of Osteoporosis" (ESOPO) on risk of the general population of Italy. We report the data on 2727 premenopausal women aged 40-50 years who are still regularly menstruating. Bone stiffness (called simplicity stiffness), which is derived from the values of broadband ultrasound attenuation (BUA) and speed of sound (SoS), was measured by a heel QUS device (Achilles Apparatus, Lunar, Co. USA). The most commonly recognized determinants of bone mass were modelled with stiffness by multiple regression analysis or analysis of variance (ANOVA). Bone stiffness was negatively related to age and number of cigarettes and positively to body weight, body weight at 25 years, height and estimated daily calcium intake. By multiple regression analysis, independent, positive, predictors of bone stiffness were age, weight at 25 years and daily calcium intake. Bone stiffness adjusted for age and body weight at 25 years was positively associated with outdoor activity score and negatively with number of pregnancies, chronic use of any drug, smoking and subjective health status. Bone stiffness was also somewhat (p < 0.015) negatively related to history of prolonged bedrest and thyroxin use. In conclusion, our results indicate that risk factors usually associated in other studies with DXA-BMD in elderly women are also associated with calcaneal bone stiffness, as measured by QUS in premenopausal women. These findings should help to identify premenopausal women at risk and to design an early strategy for osteoporosis prevention based on eliminating modifiable risks.

Effects of potassium citrate supplementation on bone metabolism.

Western diets rich in animal protein result in long-term acid loading that, despite corresponding increases in net renal acid excretion, may induce a chronic state of acidemia. This may have deleterious effects on both the kidney and bone, by increasing the risk of calcium stone in the former and leading to chemical dissolution of mineral alkaline salts in the latter. Whereas supplementation with alkaline citrate has been shown to reduce stone recurrences, its effect on bone turnover has received less attention. The aim of the present study was to evaluate whether potassium citrate favorably affects bone turnover markers in postmenopausal females with low bone density. Thirty women, aged 58 +/- 8.1 years, were enrolled and studied on basal conditions and after a 3-month course of potassium citrate supplementation (0.08-0.1 g/kg b.w. daily). Twenty-two women concluded the study while 8 withdrew. Twenty-four age-matched healthy women were taken as control cases. All were evaluated for electrolyte and acid-base balance-related parameters, bone turnover, markers and renal function. A significant decrease in net acid excretion was observed upon citrate supplementation, and this was paralleled by a significant decrease of urinary deoxypyridinolines, hydroxyproline-to-creatinine ratios, and, to a lesser extent, serum osteocalcin. Percent variations of urine citrate were inversely related to those of deoxypyridinolines and hydroxyproline. No change in these chemistries occurred in the control group. Our results suggest that treatment with an alkaline salt, such as potassium citrate, can reduce bone resorption thereby contrasting the potential adverse effects caused by chronic acidemia of protein-rich diets.

Hypoparathyroidism and co-existing celiac disease.

A 62-yr-old woman with idiopathic hypoparathyroidism was admitted to our hospital for severe anemia (Hb 5.6 gr/dl) and hypoalbuminemia (3.2 gr/dl). Hypoparathyroidism was diagnosed when she was 33 yr old, because of repeated hypocalcemic tetanic crises, low calcium and high phosphate levels. Since then she has been treated with oral calcium gluconate and calcitriol, with satisfactory clinical balance and normalization of calcium serum levels. After menopause, despite this therapy, the patient still had frequent hypocalcemic tetanic crises, resolving with iv administration, in high doses, of calcium gluconate. The anemia, for which the patient came to our attention, was hypochromic microcytic and in the past she had been treated with iron and transfusion therapy. The patient's recent history also revealed recurrent long lasting episodes of diarrhea, hyporexia and weight loss. The clinical presentation seemed related to a malabsorption syndrome: a celiac disease (CD) diagnosis was confirmed, based upon the finding, at duodenal biopsy, of a severe villous atrophy. A bone mineral density (BMD) evaluation showed a limited reduction of femoral values classified as osteopenia according to the World Health Organization (WHO) criteria. Thereafter, the patient was instructed to follow a gluten-free diet which rapidly led to an improvement of the nutritional parameters and to a reduction of calcium and vitamin D requirements. Difficult clinical and metabolic control in hypoparathyroidism patients may suggest the possible co-existence of both endocrine and extra-endocrine autoimmune diseases, such as CD. Moreover, bone density, normally reduced in celiac patients, seems to be preserved (maintained) by the lack of parathyroid secretion.