Diagnosis and management of bone fragility in diabetes: an emerging challenge.

Fragility fractures are increasingly recognized as a complication of both type 1 and type 2 diabetes, with fracture risk that increases with disease duration and poor glycemic control. Yet the identification and management of fracture risk in these patients remains challenging. This review explores the clinical characteristics of bone fragility in adults with diabetes and highlights recent studies that have evaluated bone mineral density (BMD), bone microstructure and material properties, biochemical markers, and fracture prediction algorithms (i.e., FRAX) in these patients. It further reviews the impact of diabetes drugs on bone as well as the efficacy of osteoporosis treatments in this population. We finally propose an algorithm for the identification and management of diabetic patients at increased fracture risk.

Identification and management of patients at increased risk of osteoporotic fracture: outcomes of an ESCEO expert consensus meeting.

Osteoporosis represents a significant and increasing healthcare burden in Europe, but most patients at increased risk of fracture do not receive medication, resulting in a large treatment gap. Identification of patients who are at particularly high risk will help clinicians target appropriate treatment more precisely and cost-effectively, and should be the focus of future research. INTRODUCTION: The purpose of the study was to review data on the identification and treatment of patients with osteoporosis at increased risk of fracture. METHODS: A working group convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis met to review current data on the epidemiology and burden of osteoporosis and the patterns of medical management throughout Europe. RESULTS: In Europe in 2010, the cost of managing osteoporosis was estimated at €37 billion and notably the costs of treatment and long-term care of patients with fractures were considerably higher than the costs for pharmacological prevention. Despite the availability of effective treatments, the uptake of osteoporosis therapy is low and declining, in particular for secondary fracture prevention where the risk of a subsequent fracture following a first fracture is high. Consequently, there is a significant treatment gap between those who would benefit from treatment and those who receive it, which urgently needs to be addressed so that the burden of disease can be reduced. CONCLUSIONS: Implementation of global fracture prevention strategies is a critical need. Future research should focus on identifying specific risk factors for imminent fractures, periods of high fracture risk, patients who are at increased risk of fracture and therapies that are most suited to such high-risk patients and optimal implementation strategies in primary, secondary and tertiary care.

Clinical presentation and management of patients with primary hyperparathyroidism of the Swiss Primary Hyperparathyroidism Cohort: a focus on neuro-behavioral and cognitive symptoms.

PURPOSE: To describe the clinical and biochemical profile of patients with primary hyperparathyroidism (PHPT) of the Swiss Hyperparathyroidism Cohort, with a focus on neurobehavioral and cognitive symptoms and on their changes in response to parathyroidectomy. METHODS: From June 2007 to September 2012, 332 patients were enrolled in the Swiss PHPT Cohort Study, a nationwide prospective and non-interventional project collecting clinical, biochemical, and outcome data in newly diagnosed patients. Neuro-behavioral and cognitive status were evaluated annually using the Mini-Mental State Examination, the Hospital Anxiety and Depression Scale, and the Clock Drawing tests. Follow-up data were recorded every 6 months. Patients with parathyroidectomy had one follow-up visit 3-6 months' postoperatively. RESULTS: Symptomatic PHPT was present in 43 % of patients. Among asymptomatic patients, 69 % (131/189) had at least one of the US National Institutes for Health criteria for surgery, leaving thus a small number of patients with cognitive dysfunction or neuropsychological symptoms, but without any other indication for surgery. At baseline, a large proportion showed elevated depression and anxiety scores and cognitive dysfunction, but with no association between biochemical manifestations of the disease and test scores. In the 153 (46 %) patients who underwent parathyroidectomy, we observed an improvement in the Mini-Mental State Examination (P = 0.01), anxiety (P = 0.05) and depression (P = 0.05) scores. CONCLUSION: PHPT patients often present elevated depression and anxiety scores and cognitive dysfunction, but rarely as isolated manifestations. These alterations may be relieved upon treatment by parathyroidectomy.

[FLS - three letters alter secondary fracture prevention]. / FLS - Drei Buchstaben verändern die sekundäre Frakturprävention.

The increasing importance of preventive measures in the field of orthopedics and trauma surgery becomes apparent because of the demographic changes and the high risk for secondary fractures following osteoporotic fractures. Within the fracture treatment chain, orthopedics and trauma surgery are in the "pole position" to initiate these measures in geriatric patients. In the past orthopedists and trauma surgeons have constantly accused of neglecting secondary fracture prevention in fragility fracture patients. There are several reasons that speak in favor of us undertaking a role in secondary fracture prevention: osteoporosis medication is highly effective in fracture prevention when correctly indicated, the positive effects of osteoporosis therapy on fracture healing and legal issues. Arguments that have been used to justify neglect of secondary fracture prevention are undesired side effects related to osteoporosis medications, such as atypical femoral fractures and osteonecrosis of the jaws, interference of some specific drugs with fracture healing and the working conditions in emergency departments. These run contrary to the consideration of chronic diseases such as osteoporosis, secondary osteoporosis and the underlying disease could be overlooked and the increasing complexity of medicinal osteoporosis therapy. In the first part of the article these arguments are weighed against each other. In the second part the concept of a fracture liaison service (FLS) is discussed. The FLS framework now allows an active role to be taken with respect to secondary fracture prevention despite the busy daily routine schedule. Implementation of an FLS is facilitated by dedicated instruction protocols and programs. Self-financing of an FLS is currently possible only in some specific healthcare systems. In healthcare systems in German-speaking areas a cross-financing must be available and the value of an FLS indirectly presented. Apart from the financial aspects, implementation of a FLS is also worthwhile because it can be looked on as the future driving force of innovation.

Effect of ibandronate on spontaneous osteonecrosis of the knee: a randomized, double-blind, placebo-controlled trial.

UNLABELLED: Based on this double-blind, placebo-controlled study, ibandronate has no beneficial effect on clinical and radiological outcome in patients with spontaneous osteonecrosis of the knee over and above anti-inflammatory medication. INTRODUCTION: Observational studies suggest beneficial effects of bisphosphonates in spontaneous osteonecrosis (ON) of the knee. We investigated whether ibandronate would improve clinical and radiological outcome in newly diagnosed ON. METHODS: In this randomized, double-blind, placebo-controlled trial, 30 patients (mean age, 57.3 ± 10.7 years) with ON of the knee were assigned to receive either ibandronate (cumulative dose, 13.5 mg) or placebo intravenously (divided into five doses 12 weeks). All subjects received additional treatment with oral diclofenac (70 mg) and supplementation with calcium carbonate (500 mg) and vitamin D (400 IU) to be taken daily for 12 weeks. Patients were followed for 48 weeks. The primary outcome was the change in pain score after 12 weeks. Secondary endpoints included changes in pain score, mobility, and radiological outcome (MRI) after 48 weeks. RESULTS: At baseline, both treatment groups (IBN, n = 14; placebo, n = 16) were comparable in relation to pain score and radiological grading (bone marrow edema, ON). After 12 weeks, mean pain score was reduced in both ibandronate- (mean change, -2.98; 95% CI, -4.34 to -1.62) and placebo- (-3.59; 95% CI, -5.07 to -2.12) treated subjects (between-group comparison adjusted for age, sex, and osteonecrosis type, p = ns). Except for significant decrease in bone resorption marker (CTX) in ibandronate-treated subjects (p < 0.01), adjusted mean changes in all functional and radiological outcome measures were comparable between treatment groups after 24 and 48 weeks. CONCLUSIONS: In patients with spontaneous osteonecrosis of the knee, bisphosphonate treatment (i.e., IV ibandronate) has no beneficial effect over and above anti-inflammatory medication.

[Swiss guidance for the diagnosis and management of osteoporosis]. / Recommandations de l'ASCO pour la prise en charge des patients avec ostéoporose.

Osteoporosis repesents a major health problem in the aging population requiring to take care of an increasing number of patients affected by the disease. Efficacious treatment possibilities are available. However for targeting treatment, easily accessible tools for assessing fracture risk in clinical practice are required. Until recently fracture risk prediction was mainly based on bone mineral density assessed by DXA. Recently the WHO fracture risk assessment tool FRAX has become available offering the possibility to assess individual fracture probability without additional costs. This should allow one to better identify the subjects with increased fracture risk and offering them effective treatment.

Decreased bone turnover in children and adolescents with well controlled type 1 diabetes.

AIM: Osteoporosis is a common long-term complication of type 1 diabetes (T1DM). We aimed to determine whether bone mineral density (BMD) and turnover are already altered during childhood. PATIENTS AND METHODS: We recruited 27 T1DM children and 32 controls (age 10.5 +/- 2.5 yr.) and measured BMD (dual-energy x-ray absorptiometry); bone biomarkers levels (osteocalcin: OC; procollagen type 1 propeptides amino-terminal: PINP; crosslinking telopeptides of type 1 collagen C-terminal: CTX), glycated hemoglobin (HbA1c), dietary intake and physical activity. RESULTS: Patients with T1DM had lower levels of OC (70.3 +/- 3.3 vs 105.3 +/- 6.8), PINP (556.4 +/- 47.6 vs 716.3 +/- 53.8), CTX(0.97 +/- 0.07 vs 1.20 +/- 0.08), physical activity, and calcium intake. Biomarkers were negatively correlated with HbA1c. Though, BMD was similar among groups and not related to HbA1c, disease duration, physical activity or dietary intakes. CONCLUSIONS: Bone turnover is altered in T1DM children, whereas BMD remains normal during growth. Physical activity and optimal calcium intakes may improve bone metabolism and delay osteoporosis.

Prospective evaluation of risk of vertebral fractures using quantitative ultrasound measurements and bone mineral density in a population-based sample of postmenopausal women: results of the Basel Osteoporosis Study.

OBJECTIVE: Prospective studies have shown that quantitative ultrasound (QUS) techniques predict the risk of fracture of the proximal femur with similar standardised risk ratios to dual-energy x-ray absorptiometry (DXA). Few studies have investigated these devices for the prediction of vertebral fractures. The Basel Osteoporosis Study (BOS) is a population-based prospective study to assess the performance of QUS devices and DXA in predicting incident vertebral fractures. METHODS: 432 women aged 60-80 years were followed-up for 3 years. Incident vertebral fractures were assessed radiologically. Bone measurements using DXA (spine and hip) and QUS measurements (calcaneus and proximal phalanges) were performed. Measurements were assessed for their value in predicting incident vertebral fractures using logistic regression. RESULTS: QUS measurements at the calcaneus and DXA measurements discriminated between women with and without incident vertebral fracture, (20% height reduction). The relative risks (RRs) for vertebral fracture, adjusted for age, were 2.3 for the Stiffness Index (SI) and 2.8 for the Quantitative Ultrasound Index (QUI) at the calcaneus and 2.0 for bone mineral density at the lumbar spine. The predictive value (AUC (95% CI)) of QUS measurements at the calcaneus remained highly significant (0.70 for SI, 0.72 for the QUI, and 0.67 for DXA at the lumbar spine) even after adjustment for other confounding variables. CONCLUSIONS: QUS of the calcaneus and bone mineral density measurements were shown to be significant predictors of incident vertebral fracture. The RRs for QUS measurements at the calcaneus are of similar magnitude as for DXA measurements.

[Thiazolidinediones and skeletal health]. / Thiazolidinediones et ostéoporose.

The insulin-sensitizing thiazolidinediones are effective drugs to achieve glycemic control in patients with type 2 diabetes. Results from preclinical studies have demonstrated that activation of PPAR-gamma inhibits primarily bone formation by diverting mesenchymal stem cells to the adipocytic rather than to the osteogenic lineage. In humans studies demonstrated accelerated bone loss, impaired bone mineral density as well as an increased fracture risk for thiazolidinedione users, mostly for women. As a consequence of these observations, clinicians have to carefully assess the fracture risk in patients with type 2 diabetes before starting a therapy with thiazolidinediones.

Elevation of plasma epinephrine concentrations inhibits proteolysis and leucine oxidation in man via beta-adrenergic mechanisms.

The role of elevated plasma epinephrine concentrations in the regulation of plasma leucine kinetics and the contribution of beta-receptors were assessed in man. Epinephrine (50 ng/kg per min) was infused either alone or combined with propranolol (beta-blockade) into groups of six subjects fasted overnight; leucine flux, oxidation, and net plasma leucine forearm balance were determined during 180 min. Constant plasma insulin and glucagon concentrations were maintained in all studies by infusing somatostatin combined with insulin and glucagon replacements. Plasma leucine concentrations decreased from baseline during epinephrine infusion by 27 +/- 5 mumol/liter (P less than 0.02) due to a 22 +/- 6% decrease in leucine flux (P less than 0.05 vs. controls receiving saline) and to an increase in the metabolic clearance rate of leucine (P less than 0.02). Leucine oxidation decreased by 36 +/- 8% (P less than 0.01 vs. controls). beta-Blockade abolished the effect of epinephrine on leucine flux and oxidation. Net forearm release of leucine increased during epinephrine (P less than 0.01), suggesting increased muscle proteolysis; the fall of total body leucine flux was therefore due to diminished proteolysis in nonmuscle tissues, such as splanchnic organs. Nonoxidative leucine disappearance as a parameter of protein synthesis was not significantly influenced by epinephrine. Plasma glucose and FFA concentrations increased via beta-adrenergic mechanisms (P less than 0.001). The results suggest that elevation of plasma epinephrine concentrations similar to those observed in severe stress results in redistribution of body proteins and exerts a whole body protein-sparing effect; this may counteract catabolic effects of other hormones during severe stress.

Food fortification for bone health in adulthood: a scoping review.

Food fortification can deliver essential micronutrients to large population segments without modifications in consumption pattern, suggesting that fortified foods may be formulated for populations at risk for fragility fractures. This scoping review determined the extent to which randomized controlled studies have been carried out to test the impact of fortified foods on bone outcomes, searching PubMed for all studies using the terms 'fortified AND bone', and 'fortification AND bone'. Studies were restricted to English language, published between 1996 and June 2015. From 360 articles, 24 studies met the following criteria: human study in adults ⩾18 years (excluding pregnancy or lactation); original study of a fortified food over time, with specific bone outcomes measured pre- and post intervention. Six studies involved adults <50 years; 18 involved adults ⩾50 years. Singly or in combination, 17 studies included calcium and 16 included vitamin D. There were 1 or 2 studies involving either vitamin K, magnesium, iron, zinc, B-vitamins, inulin or isoflavones. For adults <50 years, the four studies involving calcium or vitamin D showed a beneficial effect on bone remodeling. For adults ⩾50 years, n=14 provided calcium and/or vitamin D, and there was a significant bone turnover reduction. No consistent effects were reported in studies in which addition of vitamin K, folic acid or isoflavone was assessed. Results from this scoping review indicate that up to now most studies of fortification with bone health have evaluated calcium and/or vitamin D and that these nutrients show beneficial effects on bone remodeling.

Fluoride pharmacokinetics in good and poor responders to fluoride therapy.

In this study, the relationship between fluoride pharmacokinetics and the response in spinal bone density to fluoride treatment was studied in 14 patients with primary osteoporosis treated with fluoride for at least 1 year. Serum concentrations and urinary excretion of fluoride were determined after ingestion of 10 mg fluoride as monofluorophosphate. The pharmacokinetic parameters were calculated according to a linear one-compartment open model. The fasting serum fluoride level was 8.8 +/- 0.98 mumol/liter. The peak serum fluoride level was 20.5 +/- 1.4 mumol/liter and was reached within 2 h after ingestion of fluoride. When the patients were divided into good and poor responders, based on whether they did or did not exhibit a change in spinal bone density of 13 mg/cc per year or more, we found that good responders had decreased renal fluoride clearance (-62 +/- 13%, p less than .02), increased maximum change in serum fluoride (+38 +/- 18%, p less than .01), increased extrarenal clearance (+62 +/- 57%, p less than .05) and increased change in serum alkaline phosphatase (ALP) (+241 +/- 169%, p less than 0.02) compared with poor responders. Our data suggest that one factor accounting for a good response is a relatively high serum level of fluoride. However, although the maximum change in serum fluoride was greater in good responders compared with poor responders, variations in fluoride levels could not explain all of the variation in spinal bone density. Therefore, we propose that in addition to differences in serum fluoride, other factors are also responsible for the good response.

Discriminatory ability of quantitative ultrasound parameters and bone mineral density in a population-based sample of postmenopausal women with vertebral fractures: results of the Basel Osteoporosis Study.

The discriminatory potential to classify subjects with or without vertebral fractures was tested cross-sectionally with different methods for the measurement of bone status in a population-based sample of postmenopausal women. Quantitative ultrasound (QUS) measurement at the calcaneus (Lunar Achilles, Hologic Sahara), the proximal phalanges (Igea Bone Profiler), and measurement of bone mineral density (BMD) with dual-energy X-ray absorptiometry (DXA; Lunar Expert) at several anatomic sites was performed in 500 postmenopausal women (aged 65-75 years) randomly selected from the population. In addition, 50 young female subjects (20-40 years old) had QUS measurements and served as controls to express QUS results as T-score values. Radiographs of the lumbar and thoracic spine were performed in the elderly women. Two independent radiologists reviewed the X-rays for the presence of vertebral fractures. Of 486 eligible study participants, no fracture was seen in 396 participants. Single vertebral fractures were observed in 71 subjects; 19 individuals presented multiple fractures. The overall prevalence of vertebral fractures was 18.5%. Participants without vertebral fractures were compared with subjects with vertebral fractures. Normal statistical distributions were found for all bone measurement results. Risk of vertebral fracture in subjects with no and multiple vertebral fracture was estimated using age adjusted odds ratios (ORs) for QUS and dual-energy X-ray absorptiometry (DXA) values. Each SD decrease in bone measurement increased the risk of multiple vertebral fracture by 3.0 (95% CI, 1.6-5.6) for the Achilles stiffness, by 3.8 (95% CI, 1.8-8.2) for the Sahara QUI, 2.1 (95% CI, 1.3-3.4) for the Bone Profiler amplitude-dependent speed of sound (AD-SOS), and 2.1 (95% CI, 1.2-3.9) and 2.4 (95% CI, 1.3-4.3) for DXA lumbar spine and for DXA total hip, respectively. Results of a discriminant analysis showed sensitivities between 84% and 58% and specificities between 72% and 58% for the respective DXA and QUS parameters. Optimum fracture thresholds for QUS measurements derived from this analysis were calculated also. Optimum T-score threshold values for QUS measurements tended to be higher than those for DXA measurements. However, the performance of QUS measurements is at least comparable with DXA measurements in identifying subjects with multiple vertebral fractures randomly selected from the population.

Comparison of three bone ultrasounds for the discrimination of subjects with and without osteoporotic fractures among 7562 elderly women.

UNLABELLED: Bone ultrasound measures (QUSs) can assess fracture risk in the elderly. We compared three QUSs and their association with nonvertebral fracture history in 7562 Swiss women 70-80 years of age. The association between nonvertebral fracture was higher for heel than phalangeal QUS. INTRODUCTION: Because of the high morbidity and mortality associated with osteoporotic fractures, it is essential to detect subjects at risk for such fractures with screening methods. Because quantitative bone ultrasound (QUS) discriminated subjects with osteoporotic fractures from controls in several cross-sectional studies and predicted fractures in prospective studies, QUS could be more practical than DXA for screening. MATERIAL AND METHODS: This cross-sectional and retrospective multicenter (10 centers) study was performed to compare three QUSs (two heel ultrasounds: Achilles+ [GE-Lunar] and Sahara [Hologic]; the phalanges: ultrasound DBM sonic 1200 [IGEA]) for determining by logistic regression nonvertebral fracture odds ratio (OR) in a sample of 7562 Swiss women, 75.3 +/- 3.1 years of age. The two heel QUSs measured the broadband ultrasound attenuation (BUA) and the speed of sound (SOS). In addition, Achilles+ calculated the stiffness index (SI) and the Sahara calculated the quantitative ultrasound index (QUI) from BUA and SOS. The DBM sonic 1200 measured the amplitude-dependent SOS (AD-SOS). RESULTS: Eighty-six women had a history of a traumatic hip fracture after the age of 50, 1594 had a history of forearm fracture, and 2016 had other nonvertebral fractures. No fracture history was reported by 3866 women. Discrimination for hip fracture was higher than for the other nonvertebral fractures. The two heel QUSs had a significantly higher discrimination power than the QUSs of the phalanges, with standardized ORs, adjusted for age and body mass index, ranging from 2.1 to 2.7 (95% CI = 1.6, 3.5) compared with 1.4 (95% CI = 1.1, 1.7) for the AD-SOS of DBM sonic 1200. CONCLUSION: This study showed a high association between heel QUS and hip fracture history in elderly Swiss women. This could justify integration of QUS among screening strategies for identifying elderly women at risk for osteoporotic fractures.

Development of an immunoassay for human serum osteoclastic tartrate-resistant acid phosphatase.

A tartrate-resistant acid phosphatase (TrACP), which has been suggested to be very similar to the osteoclastic TrACP, was partially purified from the spleen of a patient with hairy cell leukemia. The purification procedure consisted of carboxymethyl-Sepharose, phosphocellulose, Sephacryl S-200, and phenyl-Sepharose chromatographies. Polyclonal antibodies were generated in guinea pigs with a titer of at least 1:6000. Immunohistochemical staining of fetal rat tibia with the antisera revealed that only the lysosomes of osteoclasts, but not osteoblasts, were stained. An enzyme-linked immunosorbent assay (ELISA) was developed with the antisera. There was no cross-reactivity with 1) partially purified acid phosphatases (ACPs) from normal human and beef spleens, 2) ACPs in extracts of human osteoblastic cells, 3) purified bovine bone matrix TrACP, or 4) commercial prostatic ACP. However, extracts of giant cell bone tumors, containing large amounts of bona fide osteoclasts, showed large amounts of cross-reactive material, which diluted in parallel with the partially purified hairy cell leukemic TrACP in the ELISA. Commercial serum band 5b TrACP also displaced in parallel with the partially purified hairy cell leukemic TrACP. Immunoblotting studies revealed that the antiserum, but not nonimmune guinea pig serum, reacted with the homogeneous hairy cell leukemia splenic band 5 TrACPs, which were recently purified by our laboratory. Preliminary application of the ELISA to sera of patients with metabolic bone diseases revealed that normal healthy individuals had measurable amounts of the immunoreactive material, and patients with Paget's disease or hyperparathyroidism, who should have high bone turnover, had elevated levels of this immunoreactive material in their sera. In contrast, the level of serum osteoclastic TrACP in a patient with an acute lymphatic leukemia was normal. In summary, 1) we have shown that hairy cell leukemia splenic TrACP shares significant immunological similarity with the osteoclastic TrACP and with the serum band 5b TrACP, and 2) the ELISA holds promise for a sensitive and specific assay for bone resorption.

Growth hormone secretion dynamics in a patient with ectopic growth hormone-releasing factor production.

A female patient with acromegaly, hypercalcemia, and Zollinger-Ellison syndrome was found to have a very high plasma concentration (average 2,300 pmol/liter; normal less than 50 pmol/liter) of growth hormone-releasing factor as measured by a radioimmunoassay to human pituitary growth hormone-releasing factor-1-44. The plasma concentration of growth hormone averaged 25 mIU/liter (normal less than 5 mIU/liter) and there was no rise following an intravenous 100 micrograms bolus of human pituitary growth hormone-releasing factor-1-44. Plasma growth hormone and growth hormone-releasing factor levels were unaffected by bromocriptine, insulin-induced hypoglycemia, and sleep. A long-acting somatostatin analogue lowered both the growth hormone-releasing factor and the growth hormone levels. Thyrotropin-releasing hormone stimulation and oral glucose tolerance tests produced significant increases in plasma growth hormone levels whereas the growth hormone-releasing factor level remained unchanged, suggesting that when normal somatotrophs are exposed to maximal growth hormone-releasing factor stimulation, thyrotropin-releasing hormone becomes a secretagogue of growth hormone from the pituitary. It is proposed that in the absence of a radioimmunoassay for growth hormone-releasing factor, a lack of growth hormone response to growth hormone-releasing factor in a patient with acromegaly is compatible with a source of ectopic growth hormone-releasing factor production.

Effects of IGF-I combined with GH on glucocorticoid-induced changes of bone and connective tissue turnover in man.

Chronic glucocorticoid therapy results in negative bone and connective tissue balance. To assess the effects of GH and a combination of IGF-I and GH, 24 healthy male volunteers received in a double blind fashion either recombinant human GH (0.3 IU/kg per day s.c.), or a combination of GH (0.3 IU/kg per day s.c.) and IGF-I (80 microgram/kg per day s.c.) or placebo (saline s.c.) during 6 days of methylprednisolone (0.5 mg/kg per day) treatment. Methylprednisolone decreased serum osteocalcin concentrations during placebo treatment from 32.9+/-2.1 to 9.0+/-1.4 microgram/l (P<0.0001), indicating diminished osteoblast activity, and procollagen type I (PICP) and procollagen type III (PIIINP) to 46 and 70% of baseline respectively (P<0.005), indicating diminished bone (PICP) and soft tissue collagen synthesis (PIIINP). Urinary excretion of pyridinoline, deoxypyridinoline and hydroxyproline increased during treatment with methylprednisolone alone, indicating increased bone resorption (P<0.05 or less). The combination of GH and IGF-I resulted in a significant blunting of the methylprednisolone effect on serum PICP and PIIINP concentrations (P<0.005 or less vs placebo); this effect was in part due to IGF-I, since serum PICP concentrations decreased less in the combination group than during GH treatment alone (P<0.05). In the groups receiving GH and GH combined with IGF-I, urinary hydroxyproline excretion increased more when compared with methylprednisolone alone (P<0.05 or less). These findings demonstrate that only the combination of GH and IGF-I, but not GH alone, markedly counteracts diminished bone and body collagen synthesis caused by glucocorticoids, whereas connective tissue resorption is enhanced during treatment with GH alone and in combination with IGF-I.