Osteosarcopenia in hip fracture: taking cues from pathophysiology for clinical practice.

Hip fractures are common in older and frail adults, and the risk of adverse outcomes and mortality is significantly increased in patients affected by osteosarcopenia. Identifying particularly vulnerable subjects is a critical step to act aimed at promoting postoperative recovery and reducing the risk of adverse events. However, the diagnostic criteria that are currently used to establish the severity of osteosarcopenia are not easily applicable in patients with hip fractures and impaired mobility. In this review, the new knowledge on the pathophysiology of osteosarcopenia that provides several cues for studying biomarkers potentially useful in clinical practice is summarized. Although significant progress has been obtained in understanding the biological mechanisms leading to the involution of the bone- muscle unit, further studies are needed to identify clinically relevant biomarkers and their diagnostic accuracy in establishing the severity of the osteosarcopenia, predicting adverse outcomes, and guiding physicians in choosing appropriate therapeutic interventions.

Association between markers of bone loss and urinary lithogenic risk factors in osteopenic postmenopausal women.

In this study, we explored if urinary lithogenic risk parameters could have some application for monitoring bone health status. We recruited 20 women with postmenopausal osteopenia and a negative medical history for nephrolithiasis. Markers of lithogenic risk were evaluated on 24-h urine and fastingmorning urine. Serum levels of bone turnover markers (BTM) were measured in fasting-blood samples. We found that cross-linked telopeptide of type I collagen (CTX) was significantly correlated with 24-h calcium excretion. N-terminal propeptide of type I procollagen (PINP) correlated with 24-h excretion of potassium, calcium and citrate. CTX had considerably increased in patients with pH less than 5.5. Low citrate levels (less than 3.3 mmol/24 h) were associated with lower levels of CTX and PINP. Our findings suggest that a low-grade acidosis and some lithogenic risk factors are detectable in a proportion of patients with postmenopausal osteopenia. Further studies are necessary to confirm that this evaluation could be clinically relevant.

Role of calcium-sensing receptor in bone biology.

Extracellular calcium concentration changes are recognized by Ca++ sensing receptor (CaR), a member of the G-protein-coupled receptor family. Recently, progress has been made in the understanding of CaR functional role in bone cells, notwithstanding a lack of detailed knowledge about the identity of the cation receptors. It is generally agreed that a high extracellular calcium induces osteoblast proliferation and osteoclastogenesis inhibition. Potential implications that may be considered include a role for CaR in osteogenesis, in serum calcium homeostasis regulation, and as a factor coupling bone formation to resorption in bone remodeling. The localization of CaR in bone cells provides further knowledge of the mechanisms operating in the bone remodeling model; in fact, increased calcium gradient in the site of bone resorption favors osteoblast precursors chemotaxis and inhibits osteoclasts through the increase of [Ca++]e. In vitro data indicate that CaR is a physiological regulator of bone cells, regulating the recruitment, differentiation and survival of osteoblasts and osteoclasts. This leads to the concept that the CaR present in bone cells may be targeted by agonists or antagonists to control bone cell metabolism and bone remodeling.

Asymptomatic primary hyperparathyroidism: surgical and medical management.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, frequently asymptomatic. Notwithstanding, mild PHPT may cause adverse skeletal effects that include high bone remodeling, reduced bone mineral density (BMD), and increased fracture risk. The definitive therapy for symptomatic and asymptomatic PHPT (aPHPT) is parathyroidectomy, which has been shown to increase BMD. In patients who choose not to be treated surgically or have contraindications for surgery, medical therapy should include drugs designed to protect the skeleton and/or to lower serum calcium, such as bisphosphonates, hormone replacement, and/or calcimimetic agents. However, there are currently no fracture data for any of these options. Obviously, there is the need for larger randomized controlled trials with fractures as end-points to evaluate the efficacy of medical treatment.

Skeletal effect of natural early menopause.

It is well-known that women with spontaneous or natural early menopause (NEM) (between ages of 40 and 45 yr) experience an increased risk of overall mortality, cardiovascular diseases, osteoporosis, neurological and/or psychiatric diseases, and other sequelae. On the contrary, the role of NEM is more contentious on the long-term bone consequences. The published data highlight that NEM has an ambiguous effect on bone mineral density, and is associated with an increased incidence of fractures, likely related to other risk factors rather than to osteoporosis. Therefore, an estrogen treatment should be considered for these women, especially if osteopenia is present at age of menopause.

Salt intake, hypertension, and osteoporosis.

A high salt intake has been correlated with several pathological conditions such as hypertension, cardiovascular disease, renal calcium stones, and osteoporosis. Some of these diseases present a high prevalence in the elderly and common pathogenetic mechanisms are proposed for some of them. A high salt intake has been associated with hypertension as well as osteoporosis and one of the proposed pathogenetic mechanisms is an increased calcium excretion in urine. Urinary calcium loss induces a negative calcium balance that may predispose hypertensive subjects to developing greater bone loss. The gene which encodes for the thiazide- sensitive sodium-chloride cotransporter (NCCT) represents a possible link between hypertension and osteoporosis. Subjects heterozygous for an inactivating mutation of NCCT present a positive effect on bone density as shown by the significantly higher Z-scores at the lumbar spine and total femur. Recent clinical studies also support the benefit of ACE inhibitors in reducing fracture risk or improving bone metabolism. These data suggest that the renin-angiotensin system may be one of the several factors involved in bone metabolism. Hypertension, together with stroke, has been demonstrated to be a risk factor for osteoporosis. Although the risk associated with hypertension was limited in terms of relative risk, it may have a significant impact on the general population owing to the high prevalence of hypertension. The treatment of hypertension may thus be very useful in also giving protection against fractures.

Skeletal effects of oral anticoagulants.

Vitamin K antagonists (VKA) are often used as oral anticoagulants (OA) in order to prevent thromboembolic diseases. In bone, vitamin K reduces bone resorption and functions as a co-factor in the post-translational carboxylation of several bone proteins. Osteocalcin (OC), the most abundant of these bone matrix proteins, is produced by osteoblasts and released in small amounts in blood as a specific marker of bone formation. Carboxylated proteins have a high affinity for calcium and are important in the incorporation of calcium into bone and bone formation. The increased levels of undercarboxylated osteocalcin can bring about an alteration of the bone mineral density and the risk of fracture, even if contradictory results have been observed in several epidemiologic studies. However, some, but not all reports, find that vitamin K deficiency, induced by hydroxycoumarins, may be associated with low bone mass. Additionally, epidemiologic studies have found that the use of OA may be associated with either increased or no change in fracture risk. Such divergent results may imply that human studies are compromised by the physical illnesses for which OA were prescribed. Additional epidemiological or cohort studies are warranted in order to determine whether potential pharmacological effects of VKA on bone metabolism may have clinical consequences.

Adrenal incidentaloma: effects on bone metabolism.

The effects of clinically inapparent adrenal masses or adrenal incidentalomas (AI) on bone metabolism are a controversial clinical problem related to their activity. Most of these lesions are non-functioning tumors and only a small percentage of patients exhibits a subclinical hypercortisolism (SH). The degree of clinical appearance of SH varies with the extent of hormone overproduction. However, it is controversial, up to now, if this disorder is associated with long-term morbidity and if the treatment to reverse subtle glucocorticoid excess is beneficial. Patients with AI represent an ideal field to evaluate if alterations of bone turnover may be considered a precocious sign of an abnormal pattern of endogenous steroid secretion. Several small trials have highlighted in AI with and without SH reduced levels of osteocalcin (OC), probably due to a reducted bone formation induced by a subtle excess of glucocorticoids. In patients with AI with and without SH low levels of OC might be considered a precocious sign of an abnormal pattern of slight cortisol hypersecretion and could become one of the pivotal criteria to decide whether these tumors deserve surgical excision.

Hyperphosphatemia: effects on bone metabolism and cardiovascular risk.

Hyperphosphatemia indicates a plasma inorganic phosphate (Pi) concentration greater than 5 mg/dl in the adult and 7 mg/dl in adolescent subjects. Pi homeostasis is maintained by several mechanisms (intestinal absorption, renal excretion, balance of Pi exchanges in and out of the cells, hormonal regulation). Most of the Pi, after intestinal absorption, undergoes urinary excretion suggesting that the kidney plays a major role in the maintenance of homeostasis and plasma concentration of the Pi, modifying its reabsorption in the proximal tubule where 3 types of sodium/ phosphate cotransporters have been identified (NPT). NPT2 is crucial for the Pi reabsorption and is modulated by several hormones (PTH and vitamin D3, phosphatonins) and non-hormonal factors. The hyperphospatemia is usually due to a decrease in renal function or a PTH absence (primary or secondary hypoparathyroidism) or phosphatonin deficiency. A correct serum Pi concentration is a critical condition for maintaining the calcium-phosphate (CaxPi) product within a safe range ensuring the physiological processes of bone mineralization; an increase of CaxPi product in extracellular fluids over a critical threshold, may promote processes of extraskeletal calcification. In the last few years several studies have shown that the pathogenetic mechanisms of vascular calcification do not imply a simple deposition of calcium phosphate crystals in the wall of the vessels affected by atherosclerotic lesions, but an active process making vascular smooth cells assume functional characteristics of osteoblasts. The consequences on bone are heterogeneous according to the pathogenetic mechanisms responsible for hyperphosphatemia.

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.

Uselessness of a questionnaire for osteoporosis and role of bone mass measurements in predicting tooth loss.

AIM: We evaluated whether the number of teeth lost is associated with risk factors for osteoporosis and whether bone mass measurements can add further information. METHODS: A total of 455 healthy women were enrolled. All the subjects filled in a questionnaire on risk factors for osteoporosis. The bone mineral density (BMD) was measured both by dual X-ray absorptiometry (DXA) and quantitative ultrasound measurements (QUS). RESULTS: On the basis of the questionnaire score 65.1% of the subjects were in the low risk category, 11% in the moderate risk category, 19.3% in the fairly high risk category and 4.6% in the high risk category. Close relationships (P<0.001) were observed between bone mass loss and the questionnaire risk categories. The number of teeth lost significantly increased from normal to osteoporosis groups. High correlations were also found between osteosonographic parameters and the number of teeth lost. Among questionnaire items a significant positive correlation was found only between the number of teeth lost and both age class (P<0.001) and years since menopause (P<0.001). A multiple regression showed that only age class (P<0.001) and ultrasound bone profile index (UBPI) (P=0.041) were independently linked to tooth loss. CONCLUSIONS: The results obtained showed that age is the main determinant of tooth loss and that QUS adds further information in identifying patients at a higher risk of tooth loss.

Long-term potassium citrate therapy and bone mineral density in idiopathic calcium stone formers.

Several authors have described an association between idiopathic calcium (Ca) stone disease and bone mass reduction. Hypocitraturia is a frequent feature of urolithiasis, and alkaline citrate has been recommended as one of the choice treatments in this disease. Some evidence exists as to the positive effect of potassium (K) citrate therapy on bone mass. The aim of this work was the longitudinal evaluation of bone mineral density (BMD) changes in a group of Ca oxalate stone formers treated with K citrate for two years. Enrolled patients were 120; 109 subjects completed the study (51 males and 58 females). A metabolic study and distal radius BMD measurements were conducted both at baseline (BAS) and at the end of the study (END). BMD (0.451 +/- 0.081 vs 0.490 +/- 0.080 g/cm2), T-score (-1.43 +/- 1.02 vs -0.90 +/- 1.04), net gastrointestinal alkali absorption (40.37 +/- 50.57 vs 61.26 +/- 42.26 mEq/day), urinary citrate (2.53 +/- 1.15 vs 3.10 +/- 1.44 mmol/day) and K (58.93 +/- 22.28 vs 65.45 +/- 23.97 mmol/day) excretion significantly increased from BAS to END. Urinary Ca excretion remained unchanged from BAS to END (5.16 +/- 2.74 vs 5.57 +/- 2.85 mmol/ day). Our results indicate that long-term treatment with K citrate increases forearm BMD in idiopathic Ca stone formers. It seems probable that the alkali load provided by this drug reduces bone resorption by a buffering of the endogenous acid production. K citrate appears to be a further therapeutic opportunity for the management of osteoporosis in Ca stone formers.

Does bone mineral density predict fractures comparably in women and men?

Osteoporosis (OP) is a very common disease associated with increased morbidity, mortality and costs. For a 50-yr-old woman the lifetime risk of an osteoporotic fracture is 40%, while for a man of the same age the risk is 13%. Good evidence exists as to the correlation between bone mineral density (BMD) and fracture risk in post-menopausal women. The diagnosis of OP can be made when BMD is more >2.5 SD below the mean of normal young women (T-score < or = -2.5). In men it has not been possible, until now, to identify a definite T-score under which the diagnosis of OP can be made. Several studies produced conflicting results when they tried to answer the question as to whether males and females fracture at the same absolute BMD value. Men have a greater bone size than women even when this parameter is corrected for weight and body mass. As densitometric devices measure areal density, men appear to have a higher BMD than women. Some studies have shown that, for a given BMD, males and females have the same fracture risk, while other papers have demonstrated that fractured men have a higher BMD than fractured women. Another problem concerns the diagnosis of osteoporosis. In fact, when the T-score is calculated in men on the basis of a young female reference range the prevalence of osteoporosis can be underestimated. The official position of International Society for Clinical Densitometry (ISCD) may represent an "interim" answer in order to identify men at risk of fracture.

Alendronate reduces bone resorption in HIV-associated osteopenia/osteoporosis.

PURPOSE: To evaluate the effects of alendronate, vitamin D, and calcium supplementation on bone metabolism and bone mineral density (BMD) in both HIV-infected men and women treated with highly active antiretroviral therapy (HAART). METHOD: We performed a 52-week prospective, multicenter, randomized, open-label clinical trial. Eligible participants were on stable HAART and had BMD values at the femoral neck or lumbar spine that corresponded to a t score less than -1. Patients were randomized to receive alendronate 70 mg weekly or no alendronate; calcium 1000 mg daily and vitamin D 500 IU daily were provided to all study recipients. Primary endpoint of the study was the change in bone metabolism evaluated by N-telopeptide of type 1 collagen and bone-specific alkaline phosphatase; the secondary endpoint was BMD variation. RESULTS: 18 patients were randomized to the alendronate and 23 to the no-alendronate group (controls). The alendronate-treatment group compared to controls had a significant decrease in serum N-telopeptides, 1914 +/- 1433.4 vs. 3967 +/- 1650.5 pM/L (p = .005) after 1 year. Lumbar spine BMD increased by 4% in the alendronate group (p = .004) vs. 3.7% (p = .062) in controls, compared to baseline values. Femoral neck BMD decreased by 0.5% in the alendronate group (p = .05) and by 3.5% in the control group (p = .04). No between-groups differences for BMD were found (Delta lumbar-BMD 0.0351 +/- 0.0406 in cases and 0.0356 +/- 0.073 in controls [p = .977], Delta femoral-BMD -0.085 +/- 0.160 in cases and -0.100 +/- 0.165 in controls [p = .795]). CONCLUSION: Alendronate plus vitamin D and calcium was effective in reducing bone resorption. Alendronate improved lumbar BMD and minimized femoral BMD decrease after 52 weeks compared to treatment with vitamin D and calcium alone in patients on HAART with osteopenia/osteoporosis.

Osteoporosis and urolithiasis.

Several studies have indicated that up to 60% of idiopathic calcium stone formers present hypercalciuria. Many authors have described reduced bone mineral density (BMD) in stoneformers with hypercalciuria, but osteopenia has also been found in normocalciuric patients. Moreover, Jaeger's group found that bone mass was reduced in all patients with calcium stone disease, independently of hypercalciuria. Many factors may contribute to the pathogenesis of osteopenia in stone formers. A predominant role has been given to the low-calcium diet that is still prescribed in nephrolithiasis. Also slight metabolic acidosis, which is frequently present in stone formers eating a diet rich in animal protein, can contribute to bone loss. Finally, some authors described a pathogenetic role for cytokines, prostaglandins and vitamin D receptor gene polymorphisms.

HIV-1, HAART and bone metabolism.

Much attention has been paid to the emerging complications of HIV infection in patients receiving HAART. Recently, there emerged a potentially increased risk of bone problems like osteopenia, osteoporosis and osteonecrosis as patients live longer. It could be a drug side effect, a consequence of prolonged exposure to HIV and/or activated immune cells characteristic of HIV infection, or a consequence of immune system changes that accompany suppression of virus by the drugs. Future research should focus on the etiologic mechanisms, define the incidence and prevalence prospectively, determine the relationship with HAART (especially the rule of protease inhibitors), and help to guide management. Only when the mechanism for HIV-related versus HAART-related changes can be defined, will we be much closer to designing specific interventions.

Osteoblast behaviour in the presence of bisphosphonates: ultrastructural and biochemical in vitro studies.

OBJECTIVE: A positive balance in bone remodelling is an important goal of bone metabolism both in the presence of the osteoporotic processes characteristic of ageing and, especially, of prosthetic implants. The aim of the present work was to obtain new information about the initial steps of osteoblastic growth in an in vitro osteoblastic model in the presence of two bisphosphonates. METHODS: Experiments were performed with Alendronate and Neridronate, two molecules used in the therapy of osteoporosis. Since differentiating features into osteoblastic cells are known to parallel the presence in the cytoplasm of alkaline phosphatase and osteocalcin, we also carried out immunohistochemical typing. RESULTS: Good differentiation and osteoblastic activity were generally observed in the cells in contact with these compounds, except for 10(-4) Neridronate, where biochemical data clearly indicated its toxic effect on the cells. CONCLUSION: The detection of osteoblastic markers associated with an ultrastructural picture of correct organellar morphology in our cultures further supports the hypothesis of a metabolically positive action of these molecules on osteoblasts.

Comparative study of the influence of 3 types of mineral water in patients with idiopathic calcium lithiasis.

PURPOSE: While there is general agreement on the need to increase urinary volume in stone formers, contrasting opinions have been expressed about the hardness of water and stone incidence. We evaluate the influence of 3 types of mineral water on urinary analytes in 22 idiopathic calcium oxalate stone formers. MATERIALS AND METHODS: All patients underwent a nutritional and metabolic evaluation at baseline, and after a controlled diet including water with a high, medium or low calcium content. RESULTS: In patients who drank water with high and medium calcium contents calcium excretion increased, although the results did not reach statistical significance. In those who drank water with the highest calcium content oxalate excretion significantly decreased (p = 0.05), as did the oxalate-to-calcium ratio (p = 0.05). Moreover, these modifications did not induce relevant changes in urinary saturation. In patients who drank water with the greatest amount of bicarbonate citrate excretion increased (p = 0.03). CONCLUSIONS: Mineral water with a higher calcium content induced increased calcium excretion but significantly decreased oxalate excretion. These data are in accordance with those of others, who did not find definite evidence that hard water is more lithogenic than soft water. Furthermore, water components other than calcium can modify the tendency toward crystal formation, affecting inhibitory power and/or lithogenic salt excretion.

Ultrasound in the evaluation of osteoporosis: a comparison with bone mineral density at distal radius.

It is proven that, from a technical point of view, ultrasound transmission velocity (UTV) measurement can easily be taken at the distal end of the radius. The reproducibility of UTV is good (coefficient of variation 0.3% intraoperator and 0.5% interoperator). 248 normal and 65 osteoporotic women were then studied to establish the range of UTV values and to compare the ability of UTV and bone mineral density (BMD) measurement, taken at the same skeletal sites, to detect osteoporotic fragility. Osteoporosis was defined by the presence of atraumatic vertebral fractures on an X-ray of the spine. Ultrasound velocity averaged 1570.5 +/- 43.3 m s-1 in normal and 1519.2 +/- 15.2 m s-1 in osteoporotic women; the difference is also statistically significant (p < 0.01) for BMD. Both BMD and UTV decline after menopause and are significantly correlated with age. A weak correlation (r = 0.68) was found between UTV and BMD; this supports the thesis that ultrasound velocity measures bone mass as well as other fragility components of bone distinct from the decrease of mass. Receiver operating characteristic (ROC) curve analysis showed that UTV discriminates between normal and osteoporotic patients at least as well as radial BMD, indicating that UTV is a new available diagnostic modality which can be used to screen osteoporotic subjects.