Osteoporosis Clinical Guideline. South African Medical Association--Osteoporosis Working Group.

OBJECTIVE: This Guideline aims to improve the efficacy of both diagnostic and therapeutic interventions for osteoporosis. All health care workers are targeted in the Guideline. A rather detailed summary, which is cross-referenced to the full guideline, is provided to cater for the busy general practitioner. The motivation for the development of this Guideline is based on the facts that: Osteoporosis is a common, costly disease which carries a significant morbidity and mortality, yet is still too often regarded as an inescapable part of normal ageing. Early detection and intervention will be more cost-effective than the treatment of advanced disease. Much confusion exists regarding diagnostic criteria, the assessment of fracture risk, and therapeutic intervention thresholds. A rational approach to drug selection is seldom considered. No consensus guideline on the diagnosis and management of osteoporosis has been published in this country. OUTCOMES: Prevention of fracture and a reduction in morbidity and mortality were the major considerations in the development of this Guideline. Although no formal economic analysis was undertaken, the cost-effectiveness of diagnostic and therapeutic interventions was considered in all recommendations. EVIDENCE: A combination of descriptive, boundary (minimum standards) and algorithmic guidelines was employed. The highest level of evidence (meta-analyses, randomised and controlled studies) was used as far as possible and isolated descriptive studies and expert opinions were largely ignored. A draft guideline was developed, debated at a consensus meeting and finalised on the basis of written comments following the distribution of a second draft. METHODOLOGY: See Annexure B. RECOMMENDATIONS: In the absence of a sound health economic justification for a screening policy, it is recommended that the prevention and treatment of osteoporosis is best managed using a case-finding approach. It is recommended that clinical risk factors--related to bone mineral density (BMD), bone strength or falls--provide indications for further assessment, in particular bone mass measurement. Axial, dual energy X-ray absorptiometry (DEXA) is the preferred technique to assess BMD, to diagnose osteoporosis and to assess rates of bone loss/gain. While the four diagnostic categories proposed by the World Health Organisation (WHO, 1994) provide a practical basis to identify those at risk of fracture, cognisance should be taken of its limitations. We recommend that the BMD of both spine and hip should be measured, that the NHANES III reference data for Caucasians be used for subjects of all races (until local reference ranges for different ethnic groups are established), and that the same absolute thresholds be employed to diagnose osteoporosis in men and women. Recommendations are also made regarding indications for bone mass measurement and selected routine laboratory tests. The differences between diagnostic criteria and intervention thresholds are emphasised. The need to treat should not depend on a BMD value alone, but should also be determined by the patient's age, general health and willingness to consider treatment; the presence of clinical risk factors; prevalent vertebral fractures; and the rate of bone loss/turnover; as well as the cost-effectiveness and side-effects of available treatment. Non-pharmacological measures to improve bone strength include a balanced diet, physical exercise, limiting alcohol consumption, the avoidance of smoking and bone toxic drugs and the prevention of falls. No ideal drug can be recommended for the prevention and treatment of osteoporosis in all patients. The choice of drug is largely determined by the nature of the disease (e.g. antiresorptive agents like calcium (+/- vitamin D) for mild osteopenia, hormone replacement therapy (HRT) or bisphosphonates for moderate bone loss and the addition of a bone formation-stimulating agent in patients with more severe osteoporosis) and the pati

Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity.

1. Bioactivation of sulphamethoxazole (SMX) to chemically-reactive metabolites and subsequent protein conjugation is thought to be involved in SMX hypersensitivity. We have therefore examined the cellular metabolism, disposition and conjugation of SMX and its metabolites in vitro. 2. Flow cytometry revealed binding of N-hydroxy (SMX-NHOH) and nitroso (SMX-NO) metabolites of SMX, but not of SMX itself, to the surface of viable white blood cells. Cellular haptenation by SMX-NO was reduced by exogenous glutathione (GSH). 3. SMX-NHOH and SMX-NO were rapidly reduced back to the parent compound by cysteine (CYS), GSH, human peripheral blood cells and plasma, suggesting that this is an important and ubiquitous bioinactivation mechanism. 4. Fluorescence HPLC showed that SMX-NHOH and SMX-NO depleted CYS and GSH in buffer, and to a lesser extent, in cells and plasma. 5. Neutrophil apoptosis and inhibition of neutrophil function were induced at lower concentrations of SMX-NHOH and SMX-NO than those inducing loss of membrane viability, with SMX having no effect. Lymphocytes were significantly (P<0.05) more sensitive to the direct cytotoxic effects of SMX-NO than neutrophils. 6. Partitioning of SMX-NHOH into red blood cells was significantly (P<0.05) lower than with the hydroxylamine of dapsone. 7. Our results suggest that the balance between oxidation of SMX to its toxic metabolites and their reduction is an important protective cellular mechanism. If an imbalance exists, haptenation of the toxic metabolites to bodily proteins including the surface of viable cells can occur, and may result in drug hypersensitivity.

Bone mineral density in long-term survivors of childhood cancer.

Bone mineral density (BMD) of the lumbar spine was measured in 97 long-term survivors of childhood cancer 5-23 years after diagnosis using dual-energy X-ray absorptiometry (DXA). They had been treated for acute leukemia (n = 22), brain tumors (n = 16), lymphomas (n = 16), Wilms' tumor (n = 10), neuroblastoma (n = 7) and other cancers (n = 26). The correlations between BMD and the Z-scores for weight for height, height for age and weight for age at diagnosis and follow-up were evaluated with stepwise multiple regression. Correlations with cumulative corticosteroid and radiation dose were examined with Spearman's correlation coefficient. The number of nature of fractures were noted. A BMD Z-score of below -2 was present in 13 and a BMD Z-score of -1 to -2 in 31 children. In total, a low BMD was observed in 45% of children. Height for age at follow-up correlated significantly with BMD Z-score. Increasing doses of cranial irradiation (18-54 Gy) were associated with lower BMD (p = 0.001, Spearman). This was true also for 22 children with acute lymphoblastic leukemia (ALL) who had received 18-24 Gy cranial irradiation (p = 0.04, Spearman). Fractures occurred in 14 children following trauma. The difference in BMD Z-scores of children with and without fractures did not achieve statistical significance although the majority of the children with fractures had low BMD Z-scores. The significant inverse correlation between height for age at follow-up and BMD must be interpreted with the realization that DXA is not a volumetric measurement of BMD and that short stature is associated with a smaller skeletal mass.

Relationship between androstenedione-induced myometrial contractions and platelet-activating factor acetylhydrolase in late gestation in pregnant rhesus monkeys.

An association between platelet-activating factor (PAF) and myometrial contractions has been established. Estrogens regulate PAF activity via reduction in the activity of plasma PAF acetylhydrolase (PAF-AH), the enzyme that catalyzes PAF inactivation. Administration of androstenedione to pregnant monkeys leads to sustained increases in maternal plasma estradiol (E2), with persistent nocturnal myometrial contractions. The present study tested the hypothesis that androstenedione-induced contractions are associated with a fall in maternal plasma PAF-AH activity in monkeys. Eight monkeys (132-136 days gestation, dGA) were instrumented under halothane anesthesia with maternal vascular catheters and uterine electromyogram electrodes. At 138-142 dGA, two baseline maternal arterial samples were taken for E2 and PAF-AH measurements. The following day a continuous i.v. androstenedione infusion was started in 4 monkeys while 4 control monkeys received i.v. infusions of vehicle alone. Arterial blood sampling was repeated 1 and 3 days after the start of either infusion. Despite an increase in maternal E2 to term levels and established myometrial contractions, no change in maternal plasma PAF-AH activity occurred after androstenedione treatment. Maternal plasma E2, PAF-AH activity, and contractions remained unchanged from baseline in control monkeys. In conclusion, androstenedione-induced increases in maternal plasma E2 and myometrial contractions are not associated with a fall in maternal plasma PAF-AH specific activity.

Static bone histomorphometry in preterm and term babies.

The nature and pathophysiology of the bone loss which occurs in term and especially preterm neonates are poorly understood, and it is unclear whether this neonatal osteopenia results from impaired bone formation or increased bone resorption. This study compared the static bone histomorphometry of preterm and term babies, employing iliac crest bone biopsy specimens obtained postmortem. All the babies died within the first 6 days of life and none had any clinical, biochemical or radiologic evidence of metabolic bone disease. The trabecular bone volume, as well as static parameters of bone formation (OV/TV, OV/BV, OS/BS, OB.S/BS) did not differ significantly in preterm and term babies. Although time-spaced tetracycline labelling could not be employed in the present study, evidence of rickets was not apparent. Parameters of bone resorption in preterm babies were, however, significantly higher (p = 0.01) than those of term babies, suggesting that increased bone resorption and not impaired formation, underlies the development of osteopenia in the preterm neonate.

Protein kinase C modulates parathyroid hormone- but not prostaglandin E2-mediated stimulation of cyclic AMP production via the inhibitory guanine nucleotide binding protein in UMR-106 osteosarcoma cells.

In UMR-106 osteosarcoma cells we found that PTH activated both the cAMP/protein kinase A and the Ca(2+)-dependent phosphoinositide/protein kinase C (PKC) pathways, but prostaglandin E2 (PGE2) activated only the cAMP pathway. Activation of PKC by the phorbol ester PMA had no effect on cAMP production but enhanced PTH-stimulated cAMP production by 50% or more; the effect on PGE2-induced cAMP was negligible. Inhibition of the alpha-subunit of the inhibitory guanine nucleotide binding protein (Gi) by pertussis toxin pretreatment also enhanced PTH-mediated cAMP production but had no effect on PGE2-induced cAMP production. These results suggest that although PTH-mediated adenylate cyclase activity is regulated via both the stimulatory (Gs) and inhibitory (Gi) guanine nucleotide binding proteins, only Gs regulates PGE2-mediated adenylate cyclase activity in UMR-106 cells. Costimulation with pertussis toxin and PMA did not increase PTH-stimulated cAMP production above that obtained with PMA alone. This implies a similar target of action for pertussis toxin and PMA, that is, the alpha-subunit of Gi. The alpha-subunit of Gi was found to be a substrate for in vitro PKC phosphorylation of membrane fractions from UMR-106 cells, seen as a +/- 40 kD band on SDS-PAGE. Stimulation of in situ 32P-labeled cells with either PMA or PTH also enhanced incorporation of 32P into the 40 kD band. Using the peptide antisera AS/7 and EC/2, we showed that pertussis toxin-labeled subunits of both Gi1 alpha/Gi2 alpha and Gi3 alpha could be immunoprecipitated, respectively, but immunoprecipitation of membrane proteins after in situ phosphorylation and stimulation with PMA precipitated only Gi2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical changes in bull spermatozoa during capacitation in vitro.

To evaluate the metabolic changes of bull spermatozoa (SPZ) during capacitation in vitro, SPZ were incubated for 0, 5 or 10 hours in the presence (co-culture) and absence (control) of monolayers of bovine oviduct epithelial cells, which promote capacitation-like changes in vitro. There was little change in the oxygen uptake of the SPZ after 5 hours, but after 10 hours there was a decrease, particularly in the co-cultured sample. After 5 hours there was little change in the cyclic adenosine monophosphate (cAMP) concentration of the co-culture or control SPZ, but by 10 hours the levels of cAMP decreased in both the co-cultured and control SPZ (P=0.06). The concentration of adenosine triphosphate (ATP) was somewhat decreased after 5 hours in both the co-cultured and control SPZ and the percentage of decline was much higher after 10 hours. Overall, there was no significant change in oxygen uptake or cAMP and ATP levels specifically associated with capacitation of bull SPZ.

A previously undescribed ectodermal dysplasia of the tricho-odonto-onychial subgroup in a family.

We encountered two family members with a previously undescribed pure ectodermal dysplasia. The propositus exhibited hypotrichosis, hypodontia, focal linear dermal hypoplasia on the tip of her nose, irregular hyperpigmentation on her back, bilateral amastia and athelia, and mild nerve hearing loss. Her mother displayed similar characteristics, except for present, although hypoplastic, areolae and nipples. Both mother and daughter appeared to be clinically euhidrotic. Despite a comprehensive endocrine workup, the only abnormality detected was a suboptimal cortisol response to hypoglycemia in the propositus. Five other family members seemed to be affected. The pattern of inheritance appeared to be autosomal-dominant, with variable penetrance and expressivity.

Calcium homeostasis in chronic streptozotocin-induced diabetes mellitus in the rat.

Calcium homeostasis was studied in freely fed control, streptozotocin diabetic, long-term and short-term insulin-treated diabetic rats 7 wk after the induction of diabetes. In contrast to the short-term (5-12 day) diabetic rat model, intestinal absorption of calcium was markedly enhanced in chronically insulin-deficient animals. Moreover, conventional balance studies showed that these animals were in positive calcium balance despite severe hypercalciuria. Intestinal hyperabsorption of calcium in long-standing diabetic rats occurred despite low levels of circulating 1,25-dihydroxyvitamin D and hypercorticosteronism and was attended by hypercalcemia and suppression of both plasma parathyroid hormone (PTH) and urinary cyclic 3',5'-AMP (cAMP). Long-term insulin replacement completely normalized the intestinal hyperabsorption of calcium, corrected the plasma calcium, and significantly increased circulating PTH and urinary cAMP excretion. Insulin therapy also corrected the decreased plasma 1,25-dihydroxyvitamin D observed in untreated diabetic animals. Intestinal hyperabsorption of calcium appeared to be only partially corrected by short-term insulin therapy. The accumulated results reveal decided differences in calcium homeostasis and hormonal response between the rats with long-standing diabetes and those with diabetes of short duration.

Isolated skeletal involvement in Cushing's syndrome: response to therapy.

A 38-yr-old male presented with severe symptomatic osteopenia secondary to adrenal hyperfunction without any clinical expression of Cushing's syndrome. The predominantly axial distribution of his osteopenia and the presence of rib fractures healing with abundant callus formation, despite insignificant elevations in serum alkaline phosphatase, were characteristic of glucocorticoid excess syndromes. The histological features of the pretreatment bone biopsy were typical of those associated with excess glucocorticoids, namely decreased quantities of nonmineralized bone matrix, reflecting sites of bone formation, and an increase in the number of osteoclasts, indicating enhanced bone resorption. Six weeks after adrenalectomy, repeat bone biopsy revealed a marked increase in bone matrix synthesis and a significant decrease in bone resorption. These observations suggest that stimulators of skeletal turnover, like sodium fluoride, may be inappropriate in the initial treatment of steroid-induced osteopenia after surgical cure and that vitamin D and calcium therapy offers a more rational approach. Furthermore, the importance of the routine evaluation of adrenal function in any patient presenting with osteopenia is stressed, as well as the fact that relatively isolated skeletal involvement, classically described in micronodular adrenal disease, is not necessarily peculiar to a specific subset of the syndrome but may potentially attend any cause of glucocorticoid excess.