The relationship between gonadotrophins, gonadal hormones and bone mass in men.

OBJECTIVE: Inhibin A and B (Inh A and B), activin A (Act A) as well as FSH may play an important role in bone turnover in perimenopausal women. Data in men are lacking. The aim was to investigate the relationship between circulating concentrations of Inh B and Act A and FSH/LH/testosterone (T) and their contribution to bone mineral density (BMD) in a male population. DESIGN AND SUBJECTS: Cross-sectional case-control study of 156 men, 63 with osteoporosis and 93 controls, aged (mean [SD]) 57.7 [13.7] years. MEASUREMENTS: Areal (aBMD) was measured at the femoral neck, total hip and lumbar spine. Volumetric BMD (vBMD) was calculated at the femoral neck and lumbar spine. Risk factors were assessed including the measurement of LH/FSH/T, Inh B and Act A. RESULTS: After correction for age and body mass index (BMI), associations were found between Inh B and FSH (beta regression coefficient beta = -0.326; P < 0.0001), T (beta = -0.36; P = 0.019) and Act A (beta = -0.4; P = 0.007) and between Inh B and LH (beta = 0.23; P < 0.0001) in all patients. The controls had higher Inh B concentrations compared to the cases (Inh B: controls: 139 [86] pg/ml vs. cases 88 [51] pg/ml; P = 0.005). Act A tended to be lower in the controls (Act A: controls 0.63 [0.24] ng/ml vs. cases 0.75 [0.4] ng/ml; P = 0.056). Univariate regression analyses showed a positive association between Inh B and BMD (P < 0.01) at the lumbar spine and total hip. In contrast a negative association was seen between FSH and BMD at the lumbar spine and femoral neck (P < 0.01). In a partial multivariate regression model that included the gonadal factors only, a positive association was seen between Inh B and BMD at the hip (beta = 0.088; P = 0.04). When all hormones including the gonadotrophins were entered in a full multivariate model, FSH and LH were found to be better predictors of BMD than Inh B or Act A in the controls and cases. CONCLUSIONS: These data suggest that the gonadal peptides and gonadotrophins may play a role in the maintenance of bone mass in men. Future confirmatory longitudinal studies are needed.

Access to bone densitometry increases general practitioners' prescribing for osteoporosis in steroid treated patients.

BACKGROUND: Availability of access to bone densitometry in the UK varies widely and there are concerns as to appropriate prescribing. Studies suggest inadequate use of osteoporosis prophylaxis in steroid users, despite recent guidelines. OBJECTIVE: To examine in a case-control study whether access to bone densitometry affects GPs' osteoporosis prescribing in high risk steroid users. METHOD: 10 general practices were included, five from primary care trusts (PCTs) with access to bone densitometry and five with limited access. Patients receiving prednisolone for >3 months were identified by database search. Patients receiving no prophylaxis other than calcium and vitamin D (Ca/D) were subsequently included. Appropriate patients in five practices were offered DXA scan (cases) and review. Patients in practices without access to scans (controls) were reviewed. GPs' opinions leading to treatment were sought by structured questionnaire. RESULTS: 132 (0.12%) patients were receiving prednisolone for >/=3 months, but no osteoporosis prophylaxis other than Ca/D. Pre-study prophylaxis ranged from 18 to 36%. Of 48 patients scanned, 21 (44%) were abnormal and 18 (38%) received new treatment. 13/44 (30%) controls received new treatment. 10/21 (48%) with abnormal scans started a bisphosphonate, compared with 7/44 (16%) controls (RR = 3, p = 0.004). No difference in risk factors for fracture was found in treated and untreated controls. CONCLUSIONS: GPs were three times more likely to start potent osteoporosis treatment after abnormal scans than GPs relying on clinical information. In practice, risk factors were not adequately assessed. Database searches may identify patients needing osteoporosis prophylaxis; however, DXA enables more appropriate patient treatment.

Does active treatment of rheumatoid arthritis limit disease-associated bone loss?

OBJECTIVE: Generalized bone loss in rheumatoid arthritis (RA) is multi-factorial, with the inflammatory disease itself thought to contribute to bone loss. To study the extent to which control of disease activity affects bone turnover in RA and whether treatment with disease-modifying anti-rheumatic drugs (DMARDs) reduces bone turnover and loss of bone mass, we measured bone density and biochemical markers of bone resorption in a group of patients with active RA starting on DMARDS. METHODS: Patients with active RA were enrolled on starting a new DMARD. Patients were mobile and none took steroids or any treatment for osteoporosis. Clinical and laboratory measures of disease activity were made at 3-monthly intervals and an index of disease activity (DAS) calculated. Bone density was assessed at 0, 1 and 2 yr (Hologic QDR 4500c). Urinary deoxypyridinoline (D-PYR) and pyridinoline (PYR) were measured by ELISA at 0, 3, 6, 9 and 12 months. RESULTS: Forty patients were enrolled, mean age 59.5 (range 31-76), 26 female, 14 male, 25 had established RA, 15 had RA for <2 yr. Baseline D-PYR was elevated (8.4+/-4.55 nmol/mmol creatinine) and correlated with ESR (r=0.6, P<0.01) and DAS (r=0.4, P<0.05). On treatment ESR and DAS fell by 38.5 and 29.3%, respectively. D-PYR was reduced by 12.3% by 9 months (P<0.01). Spearman rank order correlation showed ESR to be the most significant determinant of D-PYR over 1 yr (r=0.43, P<0.001). Serial bone density was available on 21 patients. There was no significant change in BMD over the 2 yr. The change in DAS over 0-3 months showed an inverse relationship with the percent change in spine over 1 yr (r=-0.5, P=0.05). The change in D-PYR over 0-3 months was not closely related to the change in BMD at hip or spine at 1 yr. CONCLUSION: Disease activity is a significant determinant of bone turnover in RA. Bone resorption markers fall on treatment of RA with DMARDs and no change in BMD was demonstrated at 2 yr. This study suggests the need to control disease activity in RA in order to prevent systemic bone loss.

An initially double-blind controlled 96 week trial of depot methylprednisolone against oral prednisolone in the treatment of polymyalgia rheumatica.

The objective was to compare the efficacy and safety of intramuscular methylprednisolone acetate (i.m. MP) with oral prednisolone (OP) in the treatment of polymyalgia rheumatica (PMR), a common steroid-treated illness where prolonged therapy can lead to steroid side-effects. The cumulative dose with i.m. MP injections given every 3-4 weeks is considerably smaller than that with conventional OP, and may therefore be associated with fewer long-term side-effects. A hybrid design was used with an initial 12 week double-blind placebo-controlled phase followed by an open phase on active treatment up to 96 weeks. The study was multicentre hospital out-patient based and included 60 patients with untreated PMR. In the double-blind phase, either 120 mg 3-weekly i.m. MP or gradually tapering daily OP (initial dose 15 mg) were administered. In the open phase, subjects continued their active treatment with gradual tapering of the steroid dosage. The remission rate at 12, 48 and 96 weeks, and other measures of disease activity, i.e. sedimentation rate, pain and morning stiffness, and percentage of adverse reactions and serious complications such as fractures, were the main outcome measures. Sixty patients entered (30 OP:30 i.m. MP) and 49 (25 OP:24 i.m. MP) completed the study. There were similar remission rates after the double-blind phase (60.6% OP and 66.6% i.m. MP, respectively) and similar disease control in the succeeding open phase. With steroid tapering, the mean erythrocyte sedimentation rate for the entire cohort registered a significant increase in the absence of an increase in symptoms. At 96 weeks, the cumulative mean steroid dose in subjects treated with i.m. MP was equivalent to 56% that of subjects treated with OP. There were eight fractures with OP compared to one on i.m. MP. Mean weight gain was significantly greater with OP than i.m. MP (3.42 vs 0.82 kg, P < 0.005). Minor adverse reactions were similar in both groups apart from slightly increased bruising with i.m. MP. Only patients on OP reported moon face, hypertension, cataracts, back pain and depression, but the numbers were small. It is possible to achieve equivalent long-term disease control in PMR with i.m. MP compared to OP. I.m. MP was associated with far fewer fractures and lesser weight gain, presumably related to lower cumulative dose. These findings may have implications in the steroid treatment of PMR, and other rheumatic and non-rheumatic diseases.

Assessment of bone in Ehlers Danlos syndrome by ultrasound and densitometry.

OBJECTIVE: Ehlers Danlos syndrome (EDS) is an inherited disorder of connective tissue characterised by hyperextensible skin, joint laxity, and easy bruising. There are phenotypic similarities with osteogenesis imperfecta, but in EDS a tendency to fracture or altered bone mass has not previously been considered to be a cardinal feature. METHOD: This case-control design study investigates whether 23 patients with EDS had differences in fracture rates, bone mass, and calcaneal ultrasound parameters compared with age and sex matched controls. RESULTS: 23 cases of EDS (mean (SD) age 38.5 (15.5)) were compared with 23 controls (mean age 37.8 (14.5)). A significant reduction in bone density measured by dual energy x ray absorptiometry was found at the neck of femur by 0.9 SD, p = 0.05, and lumbar spine by 0.74 SD, p = 0.02. At the calcaneum, broad band ultrasound attenuation and speed of sound were significantly reduced compared with controls by 0.95 SD (p = 0.004) and 0.49 SD (p = 0.004) for broad band ultrasound attenuation and speed of sound respectively. Broad band ultrasound attenuation and speed of sound remained significantly reduced after adjusting for bone mineral density (BMD). After adjusting for functional status (HAQ), age and sex, hypermobility was inversely correlated with broad band ultrasound attenuation and SOS, but not BMD at hip or spine. Previous fracture was 10 times more common in EDS (p < 0.001), with 86.9% of patients reporting a total of 47 low impact fractures, compared with 8.7% of controls. CONCLUSION: This study has identified a tendency of EDS patients to fracture, have low bone mass and abnormal bone structure. The aetiology is likely to be multifactorial, with an inherited structural element, accentuated by immobility or reduced exercise. This is one of the first clinical studies to suggest ultrasound can detect structural differences in bone, independent of dual energy x ray absorptiometry.

The sequential analysis of T lymphocyte subsets and interleukin-6 in polymyalgia rheumatica patients as predictors of disease remission and steroid withdrawal.

CD4 and CD8 T lymphocyte subsets, the late T cell activation marker, HLA-DR, and serum interleukin-6 (IL-6) levels of 57 polymyalgia rheumatica (PMR) patients were followed over 2 yr to investigate whether they could be used to predict the safe withdrawal of steroid therapy. Cell phenotypes were studied by flow cytometry and IL-6 levels by ELISA. %CD8 cells were reduced below the normal range in PMR patients prior to steroid therapy. In 56% of patients, the %CD8 T lymphocytes failed to return to normal levels when quiescent disease allowed cessation of steroid therapy. Activated CD8 T cells, as detected by HLA-DR positivity, were above the normal range at the initiation of therapy and showed a negative correlation with %CD8 T cells. The serum concentration of IL-6 fluctuated over 24 months, and the correlation between IL-6 and erythrocyte sedimentation rate (ESR) seen prior to treatment was not seen at later intervals. The %CD8 T cell and serum IL-6 levels are not a good indicator of disease activity in PMR and are, therefore, unable to predict the safe withdrawal of steroids.

Effects of inflammation and treatment on bone turnover and bone mass in polymyalgia rheumatica.

OBJECTIVE: Polymyalgia rheumatica (PMR) has an abrupt onset of inflammatory symptoms, making it a useful model for studying the effects of inflammation in bone. PMR requires corticosteroid treatment, which may itself have a detrimental effect on bone. This study used serially measured biochemical markers of bone turnover and bone density to address the relative contributions of systemic inflammation and corticosteroid therapy to bone loss. METHODS: Fifty untreated patients with PMR were randomized to receive oral prednisolone or intramuscular methylprednisolone. Biochemical bone markers (pyridinoline [PYR], deoxypyridinoline [DPYR], procollagen type I carboxy-terminal peptide [PICP]) and bone mineral density (BMD) were measured at baseline and at 6, 12, and 24 months. RESULTS: The median disease duration at presentation was 12 weeks (range 5-32 weeks). Levels of urinary crosslinks were increased in patients with untreated PMR compared with controls (PYR 74.9 +/- 30.0 nmoles/mmole creatinine, DPYR 14.6 +/- 6.4 nmoles/mmole creatinine [mean +/- SD]; P = 0.0001); the PICP level was normal (115.0 +/- 39.0 microg/liter). With treatment, the crosslinks levels fell and PICP levels rose within 6 months (P = 0.01). Bone resorption (PYR) correlated with untreated disease activity (erythrocyte sedimentation rate [ESR]) (r = 0.5, P = 0.003) and with interleukin-6 levels (r = 0.48, P = 0.05). There was a significant reduction in BMD of both the hip and the spine after 12 months of treatment (P = 0.0002), with no difference between treatment groups. As the steroid dosage was reduced, bone mass improved. Initial ESR influenced the percent change in BMD at 1 year (r = 0.35, P = 0.05), while cumulative steroid dose, mean ESR, and type of steroid used did not. CONCLUSION: Inflammation in PMR increases bone resorption and appears to have a more detrimental effect on bone than does low-dose corticosteroid. If corticosteroids can be tapered and discontinued, bone loss in PMR can be a transient phenomenon.

Clinical and echocardiographic survey of the Ehlers-Danlos syndrome.

Cardiac abnormalities such as mitral valve prolapse (MVP) are reported to be common features of the Ehlers Danlos syndrome (EDS), and it has been suggested that the majority of patients with type IV EDS will have cardiac involvement and vascular aneurysms. However, the evidence for valve lesions is inconsistent and often based on early clinical studies using mainly M-mode echo. We studied 33 patients (six male, 27 female; median age 35 yr) with EDS (30 type I, II or III, three type IV) and 30 age- and sex-matched controls. The study assessed skin stretch and joint hypermobility using Beighton and Contompasis scores. Echocardiographic examination included standard two-dimensional views from the parasternal and apical windows, and measurement of the aorta at four sites (annulus, sinotubular junction, arch and abdominal aorta). Echocardiographic abnormalities were found in four patients (12.1%) (one atrial septal aneurysm, one tricuspid prolapse, two MVP) and two controls (6.7%). MVP was found in 6.1% of EDS patients and 7% of controls. Seven patients had previously been diagnosed as having MVP; only two were shown to have true MVP using current criteria. None of those with type IV EDS had any echocardiographic abnormality. No patients with EDS had mean aortic dimensions outside the normal range at any of the points tested. Cardiac symptoms were more frequent amongst the patients than controls (atypical chest pain 48%, P = 0.0001; palpitation 39%, P = 0.001; exertional dyspnoea 30%). A wide range of rheumatological complaints were reported (current arthralgia 75%; recent back pain 72%, P = 0.005; recurrent dislocation 72%). Contrary to earlier published observations, we have not found an increased incidence of cardiac abnormalities in EDS. This syndrome may be relatively more benign, from the cardiac point of view, than was previously thought.

The value of SPECT scans in identifying back pain likely to benefit from facet joint injection.

Lumbar facet disease is sometimes implicated in low back pain. Identification is difficult and this may account for a variable response. Single photon emission computerized tomography (SPECT) is a scanning technique which enables localization of facet joint pathology. We determined whether recognition of facet disease by this method improved the response to corticosteroid injection treatment. Fifty-eight patients with low back pain and displaying accepted clinical criteria for facet joint disease were evaluated by SPECT. Twenty-two had facetal uptake of isotope. These and the tender facet joints of 36 scan-negative patients were injected with 40 mg methylprednisolone and 1 ml 1% lignocaine under X-ray control. Pain was assessed by a blind observer using the McGill questionnaire (MGQ), Present Pain Intensity score (PPI) and a Visual Analogue Scale (VAS). VAS, PPI and MGQ were reduced in the scan-positive patients at 1 month (P = 0.05, P = 0.0005, P = 0.005) and MGQ at 3 months (P = 0.01), whilst scan-negative patients were unchanged. The percentage of scan-positive patients who reported improvement was 95% at 1 month and 79% at 3 months, significantly greater than the control group (P = 0.0005, P = 0.01). Within 6 months, pain improvement in the SPECT-positive group was no longer statistically significant. Tenderness did not correlate with increased uptake on SPECT scan. Osteoarthritis of the facets was more common in the SPECT-positive patients (P < 0.001), but did not correspond with sites of increased uptake on SPECT scan. These results suggest that SPECT can enhance the identification of back pain sufferers likely to obtain short-term benefit from facet joint injection.

Diltiazem induces remission of calcinosis in scleroderma.

There is no widely accepted treatment for the calcinosis which occurs in scleroderma and dermatomyositis. We report a case of a 62-yr-old woman with active scleroderma complicated by tuberose calcinosis. The calcinosis, which had previously been unchanged for several years, regressed over a 2-yr period during which diltiazem was used to treat hypertension. This effect could not be explained by altered disease activity or renal function but, we suggest, may be due to inhibition of calcium influx into cells. This treatment merits further evaluation.

The value of percentage of CD8+ T lymphocyte levels in distinguishing polymyalgia rheumatica from early rheumatoid arthritis.

OBJECTIVE: To determine whether the low absolute numbers and percentages of CD8 positive T cells in the circulation of patients with polymyalgia rheumatica (PMR) could be used as a new diagnostic criterion for the disease. METHODS: The % CD4 and CD8 positive T lymphocyte sub-populations were measured in 37 patients with PRM before treatment and during steroid treatment over the subsequent 2 years, in 21 patients with rheumatoid arthritis (RA), and in 27 normal (N) control subjects. RESULTS: During the study, 10 patients, who were initially diagnosed as PMR, were reclassified as having had a myalgic onset of RA (PMR-RA), according to the American College of Rheumatology criteria for the diagnosis of RA. No decreased %CD8+ T lymphocyte subset had been observed in these patients at presentation, before steroid therapy, or during treatment with steroids when compared with the RA and N groups. CONCLUSION: The measurement of %CD8+ T cell subset may provide a simple method for determining whether patients presenting with myalgia are "true" PMR or are destined to develop RA.

Intrinsic spinal cord lesions in 2 patients with ankylosing spondylitis.

Two men with longstanding ankylosing spondylitis (AS) developed spastic paraparesis. Extensive investigation failed to find a cause and it was concluded that some acute undetermined intrinsic spinal cord lesion had occurred. Similar descriptions in the past have been attributed to associated multiple sclerosis, but we suggest that the finding may represent a rare complication of AS with an unknown etiology.

Domperidone and levodopa in Parkinson's disease.

To study the absorption of levodopa and interaction with the extracerebral dopamine antagonist domperidone, 15 patients with idiopathic Parkinson's disease were given levodopa 500 mg p.o., alone, and with domperidone pre-treatment. Domperidone pretreatment (10, 20, 40 mg, p.o., i.v. or i.m.) caused a mean 12% increase in peak plasma levodopa concentration, which occurred a mean of 10 min earlier than when levodopa was given alone. Parkinsonian disability scores were improved and peak clinical response occurred 16 min earlier with domperidone than without. Domperidone slightly increases the immediate bioavailability (over 4 h) and anti-parkinsonian response to a given dose of levodopa.

Role of gonadal and adrenal steroids in the impairment of the male rat's sexual behaviour by hyperprolactinaemia.

The sexual behaviour of male rats, castrated and testosterone-implanted, declined following induction of hyperprolactinaemia by domperidone. Treatment with oestradiol benzoate did not reverse this effect, and may have accentuated it. Oestradiol also amplified domperidone-induced hyperprolactinaemia. Testosterone or dihydrotestosterone (DHT) apparently delayed, but did not prevent, the gradual deterioration in sexual behaviour (prolonged ejaculation latencies) induced by domperidone, but this effect was not confirmed statistically. Adrenalectomy, followed by cortisol replacement, failed to prevent the behavioural effects of hyperprolactinaemia. No consistent changes in serum progesterone or corticosterone could be found in hyperprolactinaemic rats in which the adrenals had not been removed. In vitro formation of DHT from precursor testosterone was reduced in the amygdalae of hyperprolactinaemic rats, but not in the hypothalamus or caudal spinal cord. Oestradiol cytosol binding was unchanged in all brain areas, except for a small but significant increase in the anterior hypothalamus. These results do not support a role for altered adrenal activity in determining the effects of high levels of prolactin on sexual behaviour. There is evidence for an impaired formation of DHT in the brain, but this may account for only part of the behavioural changes observed. It is possible that the major effect of prolactin lies in neural systems directly responsive to it, rather than in altered steroid secretion or metabolism.