Kamal Shoukri

Short-Term Risedronate Treatment in Postmenopausal Women: Effects on Biochemical Markers of Bone Turnover

Abstract: 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.

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.

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≤.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.

Presacral hematopoietic tissue : Correlation of radionuclide and MRI findings

A 68-year-old woman with evidence of vertebral compression underwent MRI that revealed a presacral mass; the area enhanced on gadolinium administration. Biopsy of the mass and the vertebra revealed blood and hematopoietic cells. Tc-99m-sulfur colloid image confirmed extramedullary hematopoiesis. The patient did not have a hemoglobinopathy, and could have an occult malignancy.

Diabetes but not psoriasis.

A 74-year-old man was admitted to hospital in February, 1999, with a presumed flare of psoriasis. He had lost his appetite, was weak, confused, and had lost weight over the past 5 months. He also had a diffuse erythematous desquamating rash which had recently become more extensive. He had had this rash for 4 years. It was thought to be atypical psoriasis. Biopsy specimens showed several findings ranging from spongiotic to psoriaform dermatitis. He had recently noticed a painful tongue that made swallowing difficult. He had had diabetes requiring insulin for 15 years. His father had had diabetes mellitus but no skin rash. There were large annular and confluent areas of erythematous erosive plaques with desquamation over his abdomen, shoulders, buttocks, groin, lower back, the backs of his thighs, and his perineum (figure). No blisters or pustules were noted though many areas were tender. He also had mucositis, beefy red glossitis, cheilitis, and inflammation of perineum and perianal area. His chest, heart, and abdomen were normal on examination. His minimental scale score was 21/30. He was anaemic (haemtocrit 31%), his white cell count was 11·2 10/L), and a ferrokinetic profile was consistent with anaemia of chronic disease (reduced total serum iron, reduced total iron binding capacity, and borderline increased ferritin). Red blood cell folate, serum vitamin B12, and mean corpuscular haemoglobin were all normal. He also had hypocholesterolaemia (2·7 mmol/L).

Postpartum granulomatous hypophysitis with sphenoid sinus involvement: A case study

OBJECTIVE To report an unusual case of granulomatous hypophysitis with sphenoid sinus involvement in a woman presenting with headaches and visual field deficits approximately 2 weeks after a normal delivery. METHODS We present the history, physical findings, hormonal assay results, pituitary imaging, surgical findings, and pathology findings at presentation and then follow-up data at several times encompassing 1 year of observation. We also performed a literature review on granulomatous hypophysitis. RESULTS A 29-year-old woman presented with headache and visual disturbances 11 days after childbirth. Magnetic resonance imaging revealed a sellar mass with suprasellar extension, compression of the optic chiasm, possible invasion of the cavernous sinuses, and sinus mucosal thickening. A subtotal resection was performed through the transsphenoidal route. Histologic examination demonstrated extensive nonvasculitic granulomatous tissue in pituitary and sphenoid mucosal samples. Investigation for known causes of granulomatous hypophysitis was negative. She required desmopressin and levothyroxine replacement postoperatively. Sequential follow-up revealed spontaneous resolution of the residual mass in 5 months. CONCLUSION Unique features of this case include the concomitant presence of granulomatous lesions in the pituitary gland and the sphenoid sinus, its manifestation in the early postpartum period, and the spontaneous resolution of the residual granulomatous lesions in both the sphenoid sinus and the sella turcica.

Luteoma of pregnancy associated with nearly complete virilization of genetically female twins.

OBJECTIVE To describe a pregnancy that was complicated by the virilization of the mother and two 46XX infants. METHODS We outline the clinical presentation and diagnosis of the virilization of a mother and her twins, reviewing pertinent literature. RESULTS We report the case of a 40-year-old Caucasian female who conceived a trichorionic triplet pregnancy through in vitro fertilization (IVF) but underwent cytoreduction at 13 weeks of gestation, leaving a diamniotic dichorionic twin pregnancy. At 16 weeks of gestation the mother experienced increasing acne, facial hair, and deepening of her voice. Due to preeclampsia, the twins were delivered via caesarean section at 33 weeks of gestation. The infants had male-appearing external genitalia (Prader score IV-V) but no palpable gonads. Congenital adrenal hyperplasia was ruled out for both twins and they were both found to have a uterus and a 46XX karyotype. Maternal testosterone level was elevated at birth (1,981 ng/dL), but the infants had normal levels. Maternal testosterone levels returned to normal after delivery, consistent with a luteoma of pregnancy, although imaging was negative for a mass. CONCLUSION This is the second reported case of complete virilization associated with a luteoma of pregnancy. Whether or not IVF and related procedures increase the risk for a luteoma and whether or not fetal reduction procedures disrupt placental aromatases and increase the risk of virilization in the face of elevated androgen levels are questions that require further research.