Diuretics and bone loss in rats with aldosteronism

OBJECTIVES: We hypothesized that the increased urinary Ca2+ and Mg2+ excretion and bone loss that accompanies aldosteronism is aggravated with furosemide and is attenuated by spironolactone. BACKGROUND: Furosemide, a loop diuretic, is commonly used in patients with congestive heart failure (CHF), in which chronic, inappropriate (dietary Na+) elevations in plasma aldosterone (ALDO) and a catabolic state that includes bone wasting are expected. METHODS: In age- and gender-matched, untreated controls, four weeks of aldosterone/salt treatment (ALDO/salt, 0.75 microg/h + 1% NaCl/0.4% KCl in drinking water), four weeks of ALDO/salt + furosemide (40 mg/kg in prepared food), and four weeks of ALDO/salt + furosemide + spironolactone (200 mg/kg/day in divided doses by twice-daily gavage), we monitored: 24-h urinary Ca2+ and Mg2+ excretion; plasma-ionized [Ca2+]o and [Mg2+]o, K+, and parathyroid hormone (PTH); and bone mineral density (BMD) in the femur. RESULTS: The ALDO/salt increased (p < 0.05) urinary Ca2+ and Mg2+ excretion (4,969 +/- 1,078 and 3,856 +/- 440 microg/24 h, respectively) compared with controls (896 +/- 138 and 970 +/- 137 microg/24 h, respectively); furosemide co-treatment further increased (p < 0.05) urinary Ca2+ and Mg2+ excretion (6,976 +/- 648 and 6,199 +/- 759 microg/24 h, respectively), whereas spironolactone co-treatment attenuated (p < 0.05) these incremental losses (4,003 +/- 515 and 3,915 +/- 972 microg/24 h). Plasma [Ca2+]o was reduced (p < 0.05) at week 4 ALDO/salt + furosemide and was accompanied by hypokalemia (<3.4 mmol/l) that were rescued by spironolactone. Plasma PTH was increased (p < 0.05) compared with controls (30 +/- 4 vs. 11 +/- 3 pg/ml, respectively), whereas BMD was decreased (p < 0.05) with ALDO/salt and ALDO/salt + furosemide, but not with spironolactone co-treatment. CONCLUSIONS: In aldosteronism, hypercalciuria and hypermagnesuria and accompanying decrease in plasma-ionized [Ca2+]o and [Mg2+]o lead to hyperparathyroidism that accounts for bone wasting. Furosemide exaggerates these losses, whereas its combination with spironolactone attenuates these responses to prevent bone loss.     

Cinacalcet and the prevention of secondary hyperparathyroidism in rats with aldosteronism

BACKGROUND: In rats receiving aldosterone/salt treatment (ALDOST), increased Ca2+ excretion leads to a fall in plasma-ionized Ca2+ and appearance of secondary hyperparathyroidism (SHPT) with parathyroid hormone (PTH)-mediated intracellular Ca2+ overloading inducing oxidative stress in diverse tissues. Parathyroidectomy prevents this scenario. Rats with ALDOST were cotreated with cinacalcet (Cina), a calcimimetic that raises the threshold of the parathyroids' Ca(2+)-sensing receptor. METHODS AND RESULTS: We monitored plasma-ionized [Ca2+]o, PTH, and total Ca2+ in heart and peripheral blood mononuclear cells (PBMC), and evidence of oxidative stress in heart, PBMC, and plasma. Cina-treated rats for 4 weeks were compared with 4 weeks of ALDOST alone and with untreated age-/gender-matched controls. In comparison to controls, ALDOST led to a fall (P < 0.05) in Ca2+ (1.16 +/- 0.01 vs 1.03 +/- 0.01 mmol/L), which was not prevented by Cina (1.01 +/- 0.03 mmol/L); a rise (P < 0.05) in plasma PTH (36 +/- 7 vs 134 +/- 19 pg/mL) that was attenuated by Cina (69 +/- 12 pg/mL); increased (P < 0.05) cardiac [Ca2+] (3.92 +/- 0.25 vs 6.78 +/- 0.35 nEq/mg FFDT) and PBMC [Ca2+]i (29.8 +/- 2.3 vs 50.2 +/- 2.3 nmol/L), each of which was prevented with Cina (3.65 +/- 0.10 nEq/mg FFDT and 32.5 +/- 6.0 nmol/L, respectively); increased cardiac MDA (0.56 +/- 0.03 vs 0.94+/-0.07 nmol/mg protein) and PBMC H2O2 production (63.5 +/- 7.5 vs 154.0 +/- 25.2 mcb) and reduced (P < 0.05) plasma alpha1-AP activity (39.8 +/- 0.6 vs 29.6 +/- 1.8 mM), each prevented by Cina (0.66 +/- 0.04 mmol/mg protein, 58.2 +/- 12.7 mcb and 37.0 +/- 1.2 mM, respectively). CONCLUSIONS: PTH-mediated intracellular Ca2+ overloading accounts for the induction of oxidative stress in diverse tissues in rats with aldosteronism and which can be prevented by Cina.     

Bone loss in diabetic patients with chronic kidney disease.

OBJECTIVE: We investigated whether loss of bone is detectable during follow-up of diabetic patients with chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: In 40 initially non-dialysed diabetic patients with CKD (isotopic glomerular filtration rate < 60 ml/min/1.73 m(2) or albumin excretion rate > 30 mg/24 h), body composition (DEXA scan) and glomerular filtration rate (GFR determined from (51)Cr-EDTA clearance) were measured at a 2-year interval, and compared by paired t-tests. RESULTS: The 40 patients, mainly with Type 2 diabetes (n = 28), were men (n = 28), aged 65 +/- 11 years, with diabetes duration 18 +/- 11 years. GFR was initially 38.0 (range 8-89) ml/min/1.73 m(2). CKD progressed during follow-up: eight started haemodialysis and GFR declined in the 32 others (P < 0.05 vs. initial). T-scores for total body (initial -0.61 +/- 1.11, final -1.11 +/- 1.40; P < 0.001) and femoral neck (initial -1.88 +/- 0.15, final -2.07 +/- 0.15; P < 0.05) declined. Ten patients were osteopaenic at baseline (no osteoporosis), whereas most were osteopaenic (n = 21, P < 0.05) and five were osteoporotic at final assessment. The 16 patients who became osteopaenic or osteoporotic during follow-up did not differ from the others for the type of diabetes, age, GFR, albumin excretion rate, HbA(1c), GFR reduction and the requirement for dialysis during follow-up. They were all men (P < 0.01 by chi-squared test), with reduced initial total body T-score (-1.20 +/- 0.82, others -0.32 +/- 1.13; P < 0.05) and a lower body mass index (24.6 +/- 4.3; others 27.7 +/- 4.3; P < 0.05). CONCLUSION: Bone loss, especially in the femoral neck, is progressive in diabetic patients with CKD.     

Bone loss in men with prostate cancer treated with gonadotropin-releasing hormone agonists

Prostate cancer is the most common visceral malignancy in men. As the tumor is testosterone dependent, a frequent treatment modality involves therapy with GnRH agonists (GnRH-a) resulting in hypogonadism. Because testosterone is essential for the maintenance of bone mass in men, we postulated that GnRH-a therapy would negatively impact skeletal integrity. We compared bone mineral density (BMD), biochemical markers of bone turnover, and body composition in 60 men with prostate cancer (19 men receiving GnRH-a therapy and 41 eugonadal men) and BMD in 197 community-living healthy controls of similar age. BMD was assessed by dual energy x-ray absorptiometry and ultrasound. Biochemical markers of bone turnover, included markers of bone resorption (urinary N-telopeptide) and bone formation markers (bone-specific alkaline phosphatase and osteocalcin). Body composition (total body fat and lean body mass) was assessed by dual energy x-ray absorptiometry. Significantly lower BMD was found at the lateral spine (0.69 +/- 0.17 vs. 0.83 +/- 0.20 g/cm(2); P < 0.01), total hip (0.94 +/- 0.14 vs. 1.05 +/- 0.16 g/cm(2); P < 0.05), and forearm (0.67 +/- 0.11 vs. 0.78 +/- 0.07 g/cm(2); P < 0.01) in men receiving GnRH-a compared with the eugonadal men with prostate cancer. Significant differences were also seen at the total body, finger, and calcaneus (all P < 0.01). BMD values in eugonadal men with prostate cancer and healthy controls were similar. Markers of bone resorption (urinary N-telopeptide) and bone formation (bone-specific alkaline phosphatase) were elevated in men receiving GnRH-a therapy compared with those in eugonadal men with prostate cancer. Men receiving GnRH-a also had a higher percent total body fat (29 +/- 5% vs. 25 +/- 5%; P < 0.01) and lower percent lean body weight (71 +/- 5% vs. 75 +/- 5%; P < 0.01) compared with eugonadal men with prostate cancer. In conclusion, men with prostate cancer receiving androgen deprivation therapy have a significant decrease in bone mass and increase in bone turnover, thus placing them at increased risk of fracture.     

Bone loss in hypothyroidism with hormone replacement. A histomorphometric study

To determine the influences of hormone replacement on bone tissue in primary hypothyroidism, a histomorphometric study on undecalcified transiliac bone specimens was performed before treatment in ten patients, during the first month of treatment in 16 patients, and after more than six months of treatment in 15 patients. There were no obvious clinical or biologic signs of excessive replacement therapy. Before treatment, trabecular resorption surfaces were lower and bone cortical thickness was increased. From as early as the first month of treatment, trabecular resorption surfaces and cortical porosity were higher than normal but cortical thickness was still increased. After more than six months of treatment there was a significant loss of trabecular (decreased trabecular bone volume) and cortical (normal mean cortical width; increased porosity) bone with hyperremodeling (increased trabecular resorption surfaces and trabecular osteoid surfaces). This osteoporosis is similar to that observed in hyperthyroidism.     

Preventing oxidative stress in rats with aldosteronism by calcitriol and dietary calcium and magnesium supplements

BACKGROUND: Prominent features of the clinical syndrome of congestive heart failure (CHF) include aldosteronism and the presence of oxidative stress. Secondary hyperparathyroidism (SHPT) accompanies aldosteronism due to increased urinary and fecal excretion of Ca. SHPT accounts for intracellular Ca overloading of diverse cells, including peripheral blood mononuclear cells (PBMC), and the appearance of oxidative stress. Parathyroidectomy or a Ca channel blocker each prevent these responses. Herein, we hypothesized calcitriol, or 1,25(OH)2D3, plus a diet supplemented with Ca and Mg (CMD) would prevent SHPT and Ca overloading of PBMC and thereby oxidative stress in these cells in rats receiving aldosterone/salt treatment (ALDOST). METHODS AND RESULTS: In rats with ALDOST for 4 weeks, without or with CMD, we monitored plasma-ionized [Ca]o and parathyroid hormone (PTH), and PBMC cytosolic-free [Ca]i and H2O2 production. Untreated, age- and gender-matched rats served as controls. Compared to controls, ALDOST led to an expected fall in plasma [Ca]o level with accompanying rise in plasma PTH level and intracellular Ca overloading of PBMC and their increased production of H2O2. CMD prevented SHPT and abrogated intracellular Ca overloading of PBMC and their increased H2O2 production. CONCLUSIONS: The appearance of SHPT in aldosteronism, induced by fallen plasma [Ca]o, leads to PTH-mediated Ca overloading of PBMC and their increased production of H2O2. SHPT in rats with aldosteronism can be prevented by calcitriol and a diet supplemented with Ca and Mg. These findings raise the prospect that the SHPT found in CHF could be managed with macro- and micronutrients.     

Bone loss in pediatric renal transplant recipients

The factors that affect bone mineral density (BMD) and the long term progress of BMD after transplantation in children is still unknown. Therefore we performed a cross-sectional study to determine BMD in 83 recipients who received living renal allotransplants in Mansoura Urology & Nephrology Center between 1981 and 2001 (mean age at transplantation 13.2 +/- 3.1 years) by dual energy x-ray absorptiometry at various time intervals up to 16 years after transplantation (mean duration after transplantation was 48 +/- 34 months, range 6-192 months). The Z-score for lumbar spine was -2.28 +/- 2.06 and -1.44 +/- 1.44 for the total body. Osteopenia/osteoporosis were present in about two thirds of our kidney transplant recipients. The significant predictors for osteopenia/osteoporosis by univariate analysis were cyclosporine based immunosuppression, the cumulative steroid dose/m2 surface area, graft dysfunction and the urinary deoxypyridinoline. Using logistic regression analysis the cumulative steroid dose/m2 surface area and the urinary deoxypyridinoline were the major significant predictors for bone loss.     

Bone loss is detected more frequently in patients with ankylosing spondylitis with syndesmophytes

OBJECTIVE: To define the relationship between bone growth (syndesmophytes) and bone loss (osteoporosis) in ankylosing spondylitis (AS). METHODS: Bone mineral density (BMD) at the spine, hip, and radius was measured by dual-energy x-ray absorptiometry (DEXA), dual-energy quantitative computed tomography (DEQCT), and peripheral quantitative computed tomography (pQCT) in 103 patients with AS. Radiographs of the lumbar spine were used to detect syndesmophytes. Patients were divided in 3 groups according to disease duration. RESULTS: Osteopenia at the hip and spine was found by DEXA in 56% and 41%, respectively, of the patients with disease duration < 5 years (n = 27), with an additional 11% and 15% having osteoporosis. In patients with a longer disease duration, > 10 years (n = 28), 29% were osteoporotic at the hip and only 4% at the lumbar spine. In contrast, using spinal DEQCT, 59% of patients with early disease were found to be osteopenic; 36% of patients with long-standing disease were osteopenic and 18% were osteoporotic. More than half the patients (55%) had syndesmophytes (n = 55). With spinal DEQCT there were more patients with syndesmophytes (63%) in the group with reduced bone density than in the group without (45%). This was similar with DEXA measurements at the hip, where 31% compared to 14% had osteoporosis, respectively. Osteocalcin was elevated in 34% of patients, but was not associated with disease activity or BMD. CONCLUSION: The majority of patients with AS had reduced bone density. The method of bone density measurement is critical and should be different depending on disease duration. The finding that more patients with syndesmophytes had reduced bone density than those without suggests that bone growth and bone loss occur in parallel, and the role of inflammation in this process warrants further investigation.     

Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs

It is known that bone mineral density (BMD) is low in men who are hypogonadal. However, the rate and sites of bone loss following testosterone deficiency are not known. The resulting hypogonadism after GnRH analog therapy for the treatment of prostate cancer allows us to examine bone loss and bone resorption immediately after testosterone withdrawal. Therefore, we examined the effects of GnRH analog treatment on bone loss and bone resorption in men with prostate cancer. BMD and serum and urine concentrations of markers of bone turnover were determined in men with prostate cancer and in age-matched controls. Measurements were taken before GnRH therapy and 6 and 12 months after instituting therapy. After 12 months of GnRH therapy, the BMD of the total hip and ultra distal radius decreased significantly (P < 0.001) in men with prostate cancer compared with the controls. The mean bone loss was 3.3% and 5.3%, respectively. The observed reduction in BMD in the spine (2.8%) and the femoral neck (2.3%) did not reach statistical significance. No significant bone loss was observed in the control subjects. The concentration of the urine marker of bone resorption, N-telopeptide, was significantly increased from baseline and from controls at both 6 and 12 months in patients treated with GnRH analog therapy compared with control subjects (P < 0.05). The concentration of a serum marker of bone formation, bone-specific alkaline phosphatase, was not significantly different from baseline or from controls at 6 and 12 months. Thus, the decreased total hip and ultra distal radius BMD and increased urinary N-telopeptide concentration after testosterone withdrawal demonstrate an increase in trabecular bone loss and enhanced bone resorption. These findings demonstrate a significant loss of bone in men with prostate cancer after receiving GnRH therapy and suggest that the total hip and radius are the preferred sites for monitoring bone loss in older men. In addition, markers of bone resorption may be helpful.     

Bone loss associated with gastrointestinal disease: prevalence and pathogenesis

Decreased bone mineral density is a frequent finding in gastrointestinal disease. Factors contributing to this are (1) malabsorption of vitamin D, calcium and possibly vitamin K and other nutrients; (2) treatment with glucocorticoids; (3) inflammatory cytokines in inflammatory bowel disease; and (4) hypogonadism induced by gastrointestinal disease. A low bone mineral density has been reported in (1) patients who have undergone gastrectomy (27-44% with Z-scores of < -1); (2) pernicious anaemia; (3) coeliac disease (8-22% with Z-scores of < -2); (4) Crohn's disease (mean 32-38% with Z-scores of < -1); and (5) ulcerative colitis (mean 23-25% with Z-scores of < -1). Reduced bone mineral density is thus prevalent in these individuals and is compounded by age related bone loss, leading to the development of severe bone disease in some patients.     

Bone loss in inflammatory arthritis: mechanisms and therapeutic approaches with bisphosphonates

The inflammatory process in rheumatoid arthritis provokes intense bone resorption, evidenced as bone erosions, juxta-articular osteopenia and generalized osteoporosis. These types of bone loss share a common pathogenesis, and the role of osteoclasts in focal bone erosion was verified in elegant animal studies. The tumour necrosis factor (TNF) family of cytokines and receptors--specifically TNF-alpha, RANKL, RANK and OPG--are dominant regulators of osteoclastic bone resorption in rheumatoid arthritis. The confirmation of the osteoclast mechanism provides new insight into the structural joint protection afforded by disease-modifying drugs and suggests innovative approaches to limit bone destruction. Emerging treatment strategies for bone disease in rheumatoid arthritis are the use of monoclonal antibodies to neutralize RANKL, and powerful bisphosphonates that target pathogenic osteoclasts.     

Bone loss after total hip arthroplasty

The aim of the present study is to evaluate periprosthetic bone loss and to compare it with the bone loss in other areas of the body. We also aim to shed light on the course of bone mineral density (BMD) in patients with cemented femoral prosthesis in comparison with those with uncemented ones. We analyzed the BMD using dual-energy X-ray absorptiometry (DEXA) in a consecutively recruited convenience sample of 50 patients with cemented and uncemented total hip arthroplasty (THA). BMD was measured within the first month after surgery as well as 1 year later. In ten of the patients (20%) previously undiagnosed osteoporosis was revealed. Osteoporosis was significantly more frequently detected in patients with cemented compared to those with uncemented femoral stem. We found a significant loss in BMD in the periprosthetic femoral region compared with no losses in other body regions (lumbar spine, radius, contralateral hip). The magnitude of this loss was the highest in Gruen-Zone 7 (mean 15.2% per year). We found no BMD loss difference between patients with cemented and uncemented prosthesis in the Gruen-Zone 2–7. In conclusion these periprosthetic losses may be due to local factors such as periprosthetic bone remodeling, as they contrast with the course of BMD in the lumbar spine, radius and not operated hip.     

Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer

CONTEXT: Although androgen deprivation therapy (ADT) for prostate cancer is associated with bone loss, little is known about when this bone loss occurs. OBJECTIVE: We postulated that men on ADT would experience the greatest bone loss acutely after initiation of ADT. DESIGN AND SETTING: We conducted a 12-month prospective study at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: We studied 152 men with prostate cancer (30 with acute ADT, < 6 months; 50 with chronic ADT, > or = 6 months; and 72 with no ADT) and 43 healthy age-matched controls. MAIN OUTCOME MEASURES: We assessed bone mineral density (BMD) of the hip, wrist, total body, and spine; body composition; and markers of bone turnover. RESULTS: After 12 months, men receiving acute ADT had a significant reduction in BMD of 2.5 +/- 0.6% at the total hip, 2.4 +/- 1.0% at the trochanter, 2.6 +/- 0.5% at the total radius, 3.3 +/- 0.5% at the total body, and 4.0 +/- 1.5% at the posteroanterior spine (all P < 0.05). Men with chronic ADT had a 2.0 +/- 0.6% reduction in BMD at the total radius (P < 0.05). Healthy controls and men with prostate cancer not receiving ADT had no significant reduction in BMD. Both use and duration of ADT were associated with change in bone mass at the hip (P < 0.05). Men receiving acute ADT had a 10.4 +/- 1.7% increase in total body fat and a 3.5 +/- 0.5% reduction in total body lean mass at 12 months, whereas body composition did not change in men with prostate cancer on chronic ADT or in healthy controls (P < 0.05). Markers of bone formation and resorption were elevated in men receiving acute ADT after 6 and 12 months compared with the other men with prostate cancer and controls (P < 0.05). Men in the highest tertile of bone turnover markers at 6 months had the greatest loss of bone density at 12 months. CONCLUSIONS: Men with prostate cancer who are initiating ADT have a 5- to 10-fold increased loss of bone density at multiple skeletal sites compared with either healthy controls or men with prostate cancer who are not on ADT, placing them at increased risk of fracture. Bone loss is maximal in the first year after initiation of ADT, suggesting initiation of early preventive therapy.