Bone health and body composition in prostate cancer: Meet-URO and AIOM consensus about prevention and management strategies.

BACKGROUND: Prostate cancer (PCa) treatments are associated with a detrimental impact on bone health (BH) and body composition. However, the evidence on these issues is limited and contradictory. This consensus, based on the Delphi method, provides further guidance on BH management in PCa. MATERIALS AND METHODS: In May 2023, a survey made up of 37 questions and 74 statements was developed by a group of oncologists and endocrinologists with expertise in PCa and BH. In June 2023, 67 selected Italian experts, belonging to the Italian scientific societies Italian Association of Medical Oncology and Italian Network for Research in Urologic-Oncology (Meet-URO), were invited by e-mail to complete it, rating their strength of agreement with each statement on a 5-point scale. An agreement ≥75% defined the statement as accepted. RESULTS: In non-metastatic hormone-sensitive PCa, the panel agreed that androgen deprivation therapy (ADT) alone implies sufficient fracture risk to warrant antifracture therapy with bone-targeting agents (BTAs) for cancer treatment-induced bone loss (CTIBL) prevention (79%). Therefore, no consensus was reached (48%) for the treatment with BTAs of patients receiving short-term ADT (<6 months). All patients receiving active treatment for metastatic hormone-sensitive PCa (75%), non-metastatic castration-resistant PCa (89%) and metastatic castration-resistant PCa (mCRPC) without bone metastases (84%) should be treated with BTAs at the doses and schedule for CTIBL prevention. All mCRPC patients with bone metastasis should be treated with BTAs to reduce skeletal-related events (94%). In all settings, the panel analyzed the type and timing of treatments and examinations to carry out for BH monitoring. The panel agreed on the higher risk of sarcopenic obesity of these patients and its correlation with bone fragility. CONCLUSIONS: This consensus highlights areas lacking major agreement, like non-metastatic hormone-sensitive prostate cancer patients undergoing short-term ADT. Evaluation of these issues in prospective clinical trials and identification of early biomarkers of bone loss are particularly urgent.

Post-diagnosis serum 25-hydroxyvitamin D concentrations in women treated for breast cancer participating in a lifestyle trial in Italy.

OBJECTIVE: To report cross-sectionally serum levels of 25-hydroxyvitamin D [25(OH)D] in women living in Italy within 12 months from breast cancer (BC) diagnosis. METHODS: Baseline data were obtained from 394 women diagnosed with primary BC, enrolled from 2016 to 2019 in a lifestyle trial conducted in Italy. Subjects' characteristics were compared between two 25(OH)D concentrations (hypovitaminosis D<20 and ≥20 ng/mL) with the Chi-squared test or Fisher's exact test for small-expected counts. Using multiple logistic regression-adjusted models, we estimated odds ratios (ORs) of hypovitaminosis D with 95% confidence intervals (CIs) in the total sample and in the unsupplemented subgroup. RESULTS: Hypovitaminosis D was found in 39% of all subjects, 60% in unsupplemented subjects, and 10% in supplemented subjects. Increasing ORs of hypovitaminosis D were found with increasing body mass index, 25-30, >30, and ≥35 versus <25 kg/m2 (ORs: 2.50, 4.64, and 5.81, respectively, in the total cohort and ORs: 2.68, 5.38, and 7.08 in the unsupplemented); living in the most southern Italian region (OR 2.50, 95%CI 1.22-5.13); and with hypertriglyceridemia (OR 2.46; 95%CI 1.16-5.22), chemotherapy history (OR 1.86, 95%CI 1.03-3.38), and inversely with anti-estrogenic therapy (OR 0.43, 95%CI 0.24-0.75) in the total sample. CONCLUSIONS: Hypovitaminosis D in women recently diagnosed with BC and participating in a lifestyle trial in Italy was widespread and highest with obesity, hypertriglyceridemia, and chemotherapy use. Considering that hypovitaminosis D is a risk factor for lower efficacy of bone density treatments and possibly BC mortality, our results suggest the need to promptly address and treat vitamin D deficiency.

Vitamin D supplementation: much ado about nothing.

The scientific interest and the number of papers dealing with vitamin D supplementation has greatly grown in the last decades. Unfortunately, expert consensus on many clinical aspects of this topic is still lacking. In addition, data coming from recent clinical trials and meta-analyses seem to strongly put into doubt the real benefit of vitamin D supplementation, on both skeletal and extra-skeletal outcomes. This is further confusing since they seem to completely contradict the considerable body of evidence provided from previous epidemiological studies. This paper aims to analyze these new data in order to shed light onto the debated issues.

The epidemiology of osteoporosis in Italian postmenopausal women according to the National Bone Health Alliance (NBHA) diagnostic criteria: a multicenter cohort study.

PURPOSE: The study was aimed at evaluating the prevalence of osteoporosis, defined by BMD and the National Bone Health Alliance (NBHA) criteria, and the prevalence of clinical risk factors for fractures in Italian postmenopausal women. METHODS: This is a cross-sectional, multicenter, cohort study evaluating 3247 postmenopausal women aged ≥ 50 and older in different areas of Italy in the period 2012-2014. All the participants were evaluated as far as anthropometrics; questionnaires for FRAX® and DeFRA calculation were administered and bone mineral density was measured at lumbar spine, femoral neck and total hip by DXA. RESULTS: The prevalence of osteoporosis, as assessed by BMD and NBHA criteria was 36.6 and 57%, respectively. Mean ± SD values of FRAX® and DeFRA were: 10.2 ± 7.3 and 11 ± 9.4 for major fractures, and 3.3 ± 4.9 and 3.9 ± 5.9 for hip fractures, respectively. Among clinical risk factors for fracture, the presence of previous fracture, particularly non-spine/non-hip fracture, parental history of hip fracture and current smoking were the most commonly observed. CONCLUSIONS: Our study showed that more that the half of postmenopausal women aged 50 and older in Italy has osteoporosis on the basis of the NBHA criteria. There is a relevant high risk of femur fracture, as assessed by the FRAX® and DeFRA and previous fracture, parental history of hip fracture and current smoking are the most common risk factors. The data should be considered particularly in relation to the need to increase prevention strategies on modifiable risk factors and therapeutic intervention.

Drug-induced osteonecrosis of the jaw: the state of the art.

Osteonecrosis of the jaw (ONJ) is a rare adverse event of antiresorptive drugs such as bisphosphonates (BP) and denosumab (DMAb). The diagnosis of ONJ is considered in cases where exposed bone in the maxillofacial region does not heal within 8 weeks in a patient previously treated with an antiresorptive agent. In patients with osteoporosis, ONJ is reported as a very rare adverse event while in oncologic patients with bone metastases or malignant hypercalcemia the incidence is significantly higher (up to the 1-10% of the patients). The pathophysiology of ONJ is still not completely understood but it is multi-factorial. ONJ is a condition associated with poor oral health, oral surgery, and use of antiresorptive agents. Prevention is of paramount importance especially in cancer patients, in whom the large majority of cases of ONJ (>90%) are reported, but it should also be considered in osteoporotic patients, especially during dental surgical procedure. Some simple prevention procedures are effective in reducing the risk of its appearance. When ONJ unfortunately occurs, the large majority of patients can be managed conservatively. In conclusion, ONJ is a rare condition associated with antiresorptive drugs. Both osteoporotic and oncologic patients should be well informed about its low absolute risk and regarding the fact that the benefits of antiresorptive therapy far outweigh this potential risk of ONJ.

Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature.

The range of osteoporosis treatments is increasingly large and, like any disease, the pharmacological management of patients should involve a risk/benefit evaluation to attain the greatest reduction in risk of fracture with the lowest incidence of adverse events. The aim of this review is to critically appraise the literature about the safety issues of the main pharmacological treatments of osteoporosis. This document is the result of a consensus of experts based on a systematic review of regulatory documents, randomized controlled trials, metaanalyses, pharmacovigilance surveys and case series related to possible adverse drug reactions to osteoporosis treatment with calcium and vitamin D supplements, bisphosphonates, strontium ranelate, selective estrogen receptor modulators, denosumab, and teriparatide. As expected, randomized controlled trials showed only the most common adverse events due to the samples size and the short observation time. Case series and observational studies are able to provide data about uncommon side effects, but in some cases a sure cause-effect relationship needs still to be confirmed. Consistently with methodological limitations, the newer drugs have a tolerance profile that has not been fully explored yet. Osteoporosis treatments showed an overall good tolerance profile with rare serious adverse events that, however, must be well known by the clinician who prescribes these drugs. The concern about possible adverse events should be weighed against the reduction of morbidity and mortality associated with a significant fracture risk reduction.

[Evidences of safety and tolerability of the zoledronic acid 5 mg yearly in the post-menopausal osteoporosis: the HORIZON project]. / Evidenze di sicurezza e tollerabilità dell'acido zoledronico 5 mg una volta all'anno nell'osteoporosi postmenopausale: il progetto HORIZON.

Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Despite evidence supporting the anti-fracture efficacy of aminobisphosphonates approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within the first year. Poor compliance is associated with negative outcomes, including increased fracture risk. Tolerability and safety are among the causes of poor compliance. Intravenous bisphosphonates avoids the gastrointestial intolerance and the complex dosing instruction of the oral route ensuring full compliance which may provide improved efficacy. However, there are some concerns regarding potent intravenous bisphosphonates as zoledronic acid with respect to tolerability, mainly the acute phase response and to safety, mainly a theoretical risk of over suppression of bone turnover, renal toxicity and osteonecrosis of the jaw. In the HORIZON study, 152 patients on active treatment (82) or placebo (70) underwent to a bone biopsy after double tetracycline labeling. Bone biopsies (iliac crest) were obtained at the final visit at month 36, 1 year after the last infusion. The biopsies were analyzed by histomorphometry on bone sections and by micro-CT (microCT) analysis. One hundred forthy-three biopsies (76 zoledronic acid, 67 placebo) had at least one microCT parameter measured and 111 were available for quantitative histomorphometry (59 zoledronic acid, 52 placebo). Micro-CT analysis of bone structure revealed higher trabecular bone volume (BV/TV), decreased trabecular separation (Tb.Sp), and a strong trend towards improvement in connectivity density in biopsies obtained from patients treated with zoledronic acid, indicating preservation of trabecular bone structure with respect to placebo. Histomorphometric analysis obtained from patients treated with zoledronic acid exhibited reduction of bone turnover, as suggested by decreased activation frequency (Ac.F) by 63%, mineralizing surface (MS/BS), bone formation rate (BFR/BV). In addition, mineral appositional rate (MAR), reflecting the bone-forming capacity of osteoblastic teams at the bone multicellular unit (BMU) level, was significantly higher in patients on active treatment. No sign of excessive suppression of bone turnover or mineralization impairment was detected, confirming the safety of the treatment with intravenous zoledronic acid once a year. These interesting findings are discussed in the article, particularly in terms of new histomorphometric results and clinical findings supporting the tolerability and safety of zoledronic acid.

STEAP mRNA detection in serum of patients with solid tumours.

STEAP was identified by the strategy of suppression subtractive hybridizations in Los Angeles prostate cancer xenografts. It is expressed in prostate and other cancers, and not in most normal tissue; it can be used as a marker to evaluate biological samples from individuals suspected of having a disease associated with STEAP dysregulation, such as cancers, and may provide prognostic information useful in defining appropriate therapeutic options. The aim of this study was to test the STEAP mRNA detection in the serum of patients with different malignant tumours by using Real-Time reverse transcription PCR. The results were compared with biological samples obtained by age-matched non-malignant donors. Our data demonstrated that STEAP mRNA is detectable in serum of patients with different solid tumours whereas it is not amplifiable in non-malignant donors. This marker revealed with the molecular method of quantitative PCR in serum, may be useful to discriminate normal and cancer patients.

[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.

Trabecular bone microarchitecture in mild primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disease. High levels of PTH cause demineralization of bone and increased risk of fracture. On the other hand, the effect of PHPT on bone structure is more ambiguous. The aim of this study was to evaluate the effect of PHPT on cancellous bone volume, structure, and microarchitecture. Thirteen transiliac biopsy specimens taken in untreated post-menopausal women aged 65+/-5 yr with primary hyperparathyroidism were compared with 13 biopsies taken in normal women aged 66+/-6 yr. None of the patients presented any other disorder affecting bone metabolism. In these samples we evaluated the direct and indirect histomorphometric parameters of bone microarchitecture using an image analysis system consisting of an epifluorescent microscope (Leica DMR) connected to an analogic 3 CCD camera (Sony DXC 390P) and a computer equipped with specific software for histomorphometric analyses. No significant differences between PHPT patients and controls in cancellous bone volume, trabecular thickness, and number were found. Two-dimensional parameters showed a preserved microarchitecture in PHPT patients. On the other hand, indirect parameters of microarchitecture [Marrow Star Volume (MSV) and Trabecular Bone Pattern Factor (TBPf)] showed a significant compromising of microarchitecture in these patients. PHPT patients have similar structural parameters to normal subjects. Concerning microarchitecture, indirect approach by MSV and TBPf shows a significant compromising of connectivity. These results can explain trabecular fragility observed in clinical studies on PHPT.

Altered bone metabolism in children infected with human immunodeficiency virus.

AIM: Data on bone homoeostasis of children infected with human immunodeficiency virus (HIV), at the time of the gain in bone mass, are very rare. To determine possible alterations in bone metabolism, 13 prepubertal vertically HIV-infected children were studied. METHODS: Viral load, CD4 count, interleukin-6 (IL-6), growth hormone, insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), acid-labile subunit (ALS), IGFBP-3 proteolysis, osteocalcin in blood and N-terminal telopeptide of type I collagen in urine were determined. Lumbar spine bone mineral density was examined by dual-energy X-ray absorptiometry. RESULTS: Low osteocalcin levels were found in all patients. Low IGF-I was found in only six children, who had low CD4 count and high IL-6 levels, with normal levels of IGFBP-3 and ALS, absent IGFBP-3 proteolysis and decreased bone mineral density, irrespective of viral load or growth. CONCLUSION: Low serum osteocalcin levels appear to be an initial warning sign of possible altered bone metabolism in HIV-infected children. However, only when the immune system becomes more seriously compromised is bone loss measurable by bone densitometry.

Early diagnosis of acute mesenteric ischemia after cardiopulmonary bypass.

BACKGROUND: The aim of this study is to identify significant risk factors and eventual clinical markers associated with acute mesenteric ischemia (AMI) after cardiopulmonary bypass. METHODS: The study was retrospectively performed on a group of 19 patients (group A) undergoing cardiac surgery between January 1991 and December 1999, who developed AMI within 30 days of their hospitalization. A control group of 48 patients (group B) was compared in order to define preoperative and operative risk factors for AMI. RESULTS: At the abdominal operation, a non-occlusive mesenteric ischemia was found in every case. In-hospital mortality was 84.2% (16/19). Compared to the control, there was a significant difference in aortic cross-clamp time (p<0.001) and use of inotropic drugs (p<0.01). Postoperatively, the studied group (group A) had a significantly higher mean value of the enzymatic serum levels at any time. CONCLUSIONS: A high index of suspicion for mesenteric ischemia after cardiopulmonary bypass should be considered in patients with conditions of hypoperfusion. The early laboratory signs of AMI might be searched during the first postoperative hours.

Prevention of bone demineralization by calcium supplementation in precocious puberty during gonadotropin-releasing hormone agonist treatment.

We have previously demonstrated a negative impact on peak bone mass in girls with precocious puberty treated with GnRH agonist (GnRHa). Several studies have shown that a high calcium intake positively influences bone mass in prepubertal girls and leads to a higher peak bone mass. The aim of this study was to evaluate the effect of calcium supplementation in girls with precocious puberty during GnRHa treatment. Forty girls affected by true central precocious puberty and treated with the GnRHa triptorelin were studied for 2 yr. After diagnosis, the patients were randomly assigned to three groups: group A, treated only with GnRHa; group B, treated for 12 months solely with GnRHa and then supplemented with calcium gluconolactate/carbonate (1 g calcium/day in two doses) for 12 months; and group C, treated from the beginning with combined GnRHa and calcium. Bone mineral density (BMD) at the lumbar spine was measured by dual energy x-ray absorptiometry at the beginning of the study and after 12 and 24 months and was expressed as the calculated true volumetric density (BMDv) in milligrams per cm3. Group A showed a decrease in absolute BMDv levels, in SD score for chronological age (CA), and even more in SD score for bone age (BA). Group B showed the same behavior during the first year, but this trend was reversed in the second year, when calcium supplementation was added to GnRHa treatment. Group C showed an increase in absolute BMDv levels and in SD score for CA and BA. BMDv variations (expressed as absolute values, SD score for CA, and SD score for BA) became statistically significant at 24 months between groups C and A (P = 0.036, P = 0.032, and P = 0.025, respectively). The behavior of the lumbar spine BMDv in the three groups is consistent with a positive effect of calcium supplementation during GnRHa treatment. In calcium-supplemented patients, the normal process of bone mass accretion at puberty is preserved despite GnRHa treatment. Therefore, the reduction in BMD during GnRHa treatment in girls with precocious puberty is at least completely reversible and preventable if calcium supplementation is associated from the beginning.

A histomorphometric long-term longitudinal study of trabecular bone loss in glucocorticoid-treated patients: prednisone versus deflazacort.

Administration of a corticosteroid with minor osteopenic effects is considered an effective prevention of glucocorticoid osteoporosis. Deflazacort, an oxazolinic derivative of prednisolone, is reported to be less harmful to cancellous bone mass than other equally effective corticosteroids. However, comparative long-term studies, particularly on trabecular bone, are needed before a smaller detrimental effect on bone of deflazacort can be unequivocally confirmed. We conducted such a prospective long-term study using histomorphometric analysis of iliac bone. For the study, 18 pairs of nonimmobilized patients, matched for age, sex, menopausal state, corticosteroid dose, and type and severity of the disease, were randomly submitted to treatment with therapeutically equivalent doses of prednisone or deflazacort. Bone biopsies from iliac crest were taken before and at various times during treatment. In order to represent the time-related trabecular bone loss and find out possible differences between patients on prednisone or deflazacort, a previously described model of bone loss kinetics was applied. No significant differences in biochemical indices of bone turnover or in histomorphometric variables between prednisone- and deflazacort-treated patients were recorded before treatment. The mean duration of treatment at the final biopsy was similar for prednisone and deflazacort (15.8 and 15.2 months, respectively). Patients showed evident clinical improvement with both treatments. Osteoid and resorption surfaces showed no significant differences throughout the observation period in any of the 18 pairs. On the contrary, both steroids induced a significant decrease in trabecular bone, although the bone loss rate induced by prednisone was significantly higher than that induced by deflazacort (P < 0.05). The kinetics of bone loss and the different osteopenic effects of the two drugs are described by the negative exponential function fitted to data from patients never previously given glucocorticoids; the model yields highly significant difference (P approximately equal to 0.01) between the two drugs and allows estimation of the difference even 3 years after the beginning of treatment (-3.0%/year versus -1.1%/year for prednisone and deflazacort, respectively). This prospective long-term study confirms that an exponential model accurately describes the trabecular bone loss induced by long-term corticosteroid treatment and demonstrates that deflazacort, at therapeutically effective doses, induces less trabecular bone loss than prednisone.

Effect of bisphosphonate therapy and parathyroidectomy on the urinary excretion of galactosylhydroxylysine in primary hyperparathyroidism.

BACKGROUND: In patients with mild or asymptomatic primary hyperparathyroidism a reliable index of bone resorption might be useful for appropriate management. Hydroxyproline is the most commonly used marker of bone resorption but its low specificity and sensitivity are known. Galactosylhydroxylysine, an amino acid mainly represented in bone collagen, has been proposed as a more suitable index of bone resorption. In this study we evaluated the sensitivity of galactosylhydroxylysine and hydroxyproline assays in following the changes of their urinary levels in 12 patients with mild primary hyperparathyroidism before and after treatment with bisphosphonate and surgery. METHODS: Serum and fasting urine specimens were obtained from 12 women with mild primary hyperparathyroidism before and after bisphosphonate treatment (2.5 mg daily for 5 days, intravenously) and after a further 25 days; in 7 patients biochemical tests were also performed 1 and 6 days after parathyroidectomy. Galactosylhydroxylysine was assayed by an HPLC method and hydroxyproline by a RIA commercial kit. RESULTS: Baseline galactosylhydroxylysine urinary levels were far above the normal range in all the patients whilst in 8 of them baseline hydroxyproline levels were normal. Bisphosphonate treatment significantly decreased bone turnover as shown by a significant fall in serum calcium (from 2.9 to 2.6 mmol/l; P < 0.001) and in galactosylhydroxylysine and hydroxyproline (-55 and -31% respectively). Twenty-five days after the end of treatment, resorption increased again and serum calcium and galactosylhydroxylysine, but not hydroxyproline, rose significantly towards basal levels. One day after parathyroidectomy serum calcium, galactosylhydroxylysine and PTH showed reduction below normal ranges. PTH and galactosylhydroxylysine returned to normal values at day 6 after parathyroidectomy. No changes in hydroxyproline levels were seen. Galactosylhydroxylysine, but not hydroxyproline, correlated significantly with serum calcium and PTH. CONCLUSION: Galactosylhydroxylysine appears to be a sensitive index of bone resorption, useful in the clinical assessment of bone involvement and in the management of patients with mild primary hyperparathyroidism.

Long-term effects of transdermal and oral estrogens on serum lipids and lipoproteins in postmenopausal women.

The transdermal and oral administration of estrogens for one year were compared with respect to the effects on lipid metabolism. Eighty-one postmenopausal women (1.5-3 years after menopause) were randomly divided into three groups. The first two groups received sequential estrogen treatment with either transdermal estradiol (Estraderm TTS, Ciba Geigy; 50 micrograms/day; 24 women) or 0.625 mg/day conjugated estrogens (Premarin, Wyeth; 20 subjects), respectively. In both groups medroxyprogesterone (10 mg/day per os) was added for 12 days of each cycle. Thirty-five subjects served as control group without therapy. No significant changes in the lipid profile was observed in control subjects after 1 year of follow-up. Serum triglycerides decreased significantly (-10.9 +/- 26% S.D.; P < 0.05) in transdermal treated women, whereas it slightly rose in oral estrogen group. Comparable significant decreases in total and low density lipoprotein (LDL) cholesterol (mean range -6.5/-18.0%) were observed in women on estrogen replacement therapy. High density lipoprotein (HDL) cholesterol significantly diminished in transdermal estradiol group, but it rose slightly in the oral estrogen group. Thus the fraction of HDL cholesterol over LDL cholesterol did not change in the transdermal group whereas it significantly rose in subjects treated with oral estrogens. It remains to be established to what extent these differences on lipid metabolism are relevant for the prevention of cardiovascular diseases.

Transdermal estradiol in the treatment of postmenopausal bone loss.

The effects on calcium metabolism and forearm bone mineral density of sequential transdermal estradiol (ESTRADERM TTS-50), 50 micrograms/day and medroxyprogesterone (10 mg/day for 12 days) was studied in a randomised controlled trial in 34 healthy females 2-4 years after the menopause. At the end of the 18 months' treatment course with transdermal estradiol, bone density was increased by 4.31% (P less than 0.01) but was decreased by 3.5% (P less than 0.01) in the control group. In the treated group, serum calcium, calcium excretion and hydroxyproline excretion significantly fell during the first 2 months with no significant changes thereafter. Serum alkaline phosphatase significantly decreased only after 4 months, it continued to fall until the fourteenth month when a plateau became apparent. Serum phosphate and tubular maximum for urinary phosphate progressively fell until the tenth month of therapy but thereafter they rose up to initial values. Serum intact parathyroid hormone did not show any significant change. In conclusion, small doses of transdermal estradiol are as effective as oral estrogens. This suggests that the bone sparing effects of estrogens may be due only to low circulating estradiol concentrations, but not to supraphysiological estrone levels. It seems also that estrogens exert both a straight inhibition of bone resorption and a partial inhibition of parathyroid responsiveness.

The use of dichloromethylene bisphosphonate and aminobutane bisphosphonate in hypercalcemia of malignancy.

54 patients with malignant hypercalcemia were treated with either dichloromethylene bisphosphonate (Cl2MBP) or aminobutane bisphosphonate (AHButBP). Both compounds infused intravenously (i.v.) were rapidly effective in lowering serum calcium to normal range and a potency ratio between Cl2MBP and AHButBP could be roughly estimated as 1:100-250. 600 mg of Cl2MBP infused in one day over 9 h in nine patients were only slightly less effective (serum calcium from 12.3 +/- 1.7 to 10.1 +/- 1.1 SE, mg/dl) than 3300 mg infused in 11 consecutive days (13.4 +/- 1.9 to 9.3 +/- 1.2 SE, mg/dl). Thus the effectiveness of treatment with Cl2MBP was related better to the overall time of infusion than to the cumulative dose administered. This could not be demonstrated in a similar trial using AHButBP. 1600 mg Cl2MBP daily p.o. was unable to prevent the relapse of hypercalcemia in four patients after a treatment course with i.v. bisphosphonates. 100 mg of Cl2MBP intramuscularly maintained serum calcium within the normal range in two out of eight patients; however, weekly infusions of either Cl2MBP or AHButBP prevented the relapse of hypercalcemia in eight similarly treated patients for several weeks. Providing that adequate dosages are adopted, parenteral Cl2MBP and AHButBP may be a useful measure for controlling hypercalcemia in patients with carcinoma.