Short-term risedronate treatment in postmenopausal women: effects on biochemical markers of bone turnover.

The development of new biochemical markers has made it possible to assess the effects of therapeutic agents on bone turnover more rapidly and precisely. In this early phase II study, we analyzed the effects of short-term, high-dose treatment with risedronate, a potent pyridinyl bisphosphonate, on markers of bone resorption and formation. Resorption markers included urinary free deoxypyridinoline (D-Pyr) crosslinks, N-terminal telopeptide (NTx) and C-terminal telopeptide (CTx) type I collagen crosslinks. Bone formation markers included osteocalcin (OC), bone-specific alkaline phosphatase (BSAP) and the C-terminal peptide of type I procollagen (PICP). All three resorption markers showed rapid, significant (p<0.05) decreases from baseline following daily administration of 30 mg risedronate for 2 weeks. The mean decreases at 2 weeks were 28% for D-Pyr, 61% for NTx and 73% for CTx, respectively. Over the next 10 weeks after treatment, D-Pyr approached baseline while NTx and CTx remained well below baseline values. The markers of bone formation showed little change during therapy but decreased significantly at 4-10 weeks after therapy - an expected outcome of bisphosphonate therapy. Moreover, there was a significant correlation between the early effects on bone resorption markers and the delayed effects on formation markers. This study demonstrates that the approved dose of risedonate (30 mg/day) for Paget's disease is effective at decreasing bone turnover after 2 weeks of treatment, as observed by the sensitive response of bone turnover markers.

The effect of short-term treatment with micronized estradiol on bone turnover and gonadotrophins in older men.

Evidence for the role of estrogen in male bone metabolism has been confirmed by studies on a man with a genetic defect in the estrogen receptor as well as men with aromatase defects. All exhibited tall stature, delayed epiphysial closure, decreased bone density and increased bone turnover. Estrogen is likely to affect bone turnover in men throughout life; therefore, we hypothesized that older men would show decreased bone resorption in response to estrogen therapy. To test our hypothesis, fourteen community-dwelling men with osteopenia of the femoral neck were treated for 9 weeks with micronized estradiol, 1 mg/d, a dose which is effective in postmenopausal women. Each subject served as his own control. Markers of bone resorption, N-terminal collagen crosslinks (NTX) and C-terminal collagen crosslinks (CTX) and markers of bone formation, osteocalcin (OC) and bone specific alkaline phosphatase (BSAP) were measured every 3 weeks during a 9-week treatment period and 9 weeks post-treatment. Sex hormones, gonadotrophins and calciotropic hormones were measured at baseline, 9 weeks on treatment and 9 weeks post- treatment. After 9 weeks of treatment, estradiol and estrone levels increased significantly by greater than 6-fold and 15-fold, respectively. SHBG levels increased significantly by 17%. Testosterone and free testosterone levels decreased significantly by 27% and 34%, respectively. Markers of bone resorption showed wide variation at baseline and while on treatment. There was no correlation between changes in bone markers and changes in estrogen levels. During treatment, 11 patients showed a decrease of NTX or CTX, but three showed an increase. These three and one other subject had high initial levels of FSH and LH, suggesting some degree of primary gonadal failure, which decreased during estrogen therapy. Thus, the change in NTX (and CTX) after 9 weeks of E2 treatment was correlated with initial FSH (r= -.66, p= .01) and LH (r= -.73, p= .003) values. In addition, the largest decrease in free testosterone at 9 weeks was correlated with the higher values for NTX, CTX and BAP (r=-0.66, -0.68, -0.70 respectively; p< or =.01 for each of the markers). Treatment was generally well tolerated. Side effects of treatment were minimal, and included breast tenderness and decreased libido which reversed after treatment. We conclude that it is feasible to give low dose estrogen to healthy older men, but that the effects on bone turnover are not consistent. Changes in central feedback and in endogenous sex hormone production may alter the response of bone turnover to exogenous estrogen in this population.

Diagnosis of osteoporosis.

Early diagnosis is the key to the prevention and treatment of osteoporosis. A healthy skeleton has intrinsic properties that confer strength to resist fracture under ordinary stress. Some of the properties that confer strength and fracture resistance include: bone mass or density and bone quality determined by skeletal composition, fine structure and spatial organization, geometric properties, and rate of remodeling. The current approach to early diagnosis of osteoporosis is based on the measurement of bone mass or bone mineral density (BMD). Low bone mass is the single most accurate predictor of increased fracture risk. BMD accounts for 70% to 80% of the future fracture risk in older white women and is a far better predictor of osteoporosis than hypertension is for stroke or total cholesterol is for cardiovascular events in men. Perhaps in the future a better understanding and quantification of bone quality will help refine our ability to identify patients at risk. BMD can be measured at a variety of skeletal sites using several different methods that have been approved by the FDA. The basic attributes of each method will be addressed in this paper, with particular attention given to the method that is currently considered the gold standard, dual energy x-ray absorptiometry. The indications for BMD testing, clinical utility of BMD, frequency of follow-up testing, correlation between the available densitometry methods, problems and pitfalls in interpretation, and features of a satisfactory densitometry report of results will all be addressed. The current role of biochemical markers of bone turnover in the diagnosis and monitoring of treatment will be discussed briefly.

Concurrence of Graves' disease and dysplastic cerebral blood vessels of the moyamoya variety.

We describe two Caucasian women with the concurrence of Graves' disease and the moyamoya phenomenon (radiological evidence of collateral cerebral blood vessels like "puffs of smoke" due to cerebrovascular occlusive disease). One patient presented with acute cerebrovascular ischemia due to Moyamoya disease shortly after radioactive iodine therapy for Graves' disease and the second presented with Graves' disease 10 years after being diagnosed with moyamoya dysplastic cerebral vessels. The optimal treatment of hyperthyroidism in these patients is unknown; however, careful control of the hyperthyroidism by any modality seems reasonable. Our limited experience suggests that antithyroid drugs and radioactive iodine therapy are rational options. Thyroidectomy appears to be a safe therapeutic alternative, although long-term efficacy may be difficult to assure. Both of our patients had to be treated twice for hyperthyroidism. Whether Graves' disease and Moyamoya coexist because of an aggressive autoimmune mechanism is a concept that remains to be settled.

Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women.

The present study was undertaken to determine whether the addition of an androgen to estrogen therapy in postmenopausal women would alter the skeletal response as determined by measurements of markers of bone formation and resorption. Postmenopausal women were treated for 9 weeks with either a combination of 1.25 mg esterified estrogen and 2.5 mg methyltestosterone (E+A) or 1.25 mg conjugated equine estrogen (CEE). Both groups showed a similar decrease in urinary excretion of the bone resorption markers, deoxypyridinoline, pyridinoline, and hydroxyproline. Patients treated with CEE showed decreases in the serum markers of bone formation, bone-specific alkaline phosphatase, osteocalcin, and C-terminal procollagen peptide. In contrast, subjects treated with E+A showed increases in these markers of bone formation. CEE increased, and E+A decreased serum levels of sex hormone-binding globulin as well as triglycerides and high density lipoprotein levels. Only CEE significantly reduced low density lipoproteins. Both regimens were effective in reducing postmenopausal somatic symptoms, but only E+A had a significant effect on psychological symptoms. We conclude that short term administration of androgen with estrogen may reverse the inhibitory effects of estrogen on bone formation. Long term studies are needed to determine the relative benefits and risks of the combination of estrogen and androgen and whether this results in greater increases in bone mass and strength.