Kashayar Sakhaee, M.D.
Professor of Medicine
Director, General Clinical Research Center
Howard Heller, M.D.
Assistant Professor of Medicine
Division of Endocrinology
I. Title of Project: Combined Treatment with Potassium citrate and Calcium
Citrate Dual Inhibition of Bone Loss by Alkali Lead and Parathyroid Suppression
Principal Investigator: Khashayar Sakhaee, M.D.
Summary: This study will compare the efficacy of combined treatment with
calcium citrate and potassium citrate with that of individual citrate salts
in preventing postmenopausal bone loss. The project will test the hypothesis
that the Co administration of calcium citrate and potassium citrate would produce
a more pronounced inhibition of bone loss, due to the effect of calcium citrate
(parathyroid suppression) and of potassium citrate (alkali load) in directly
reducing osteoclastic bone resorption.
II. Title of Project: Effect of Estrogen
Principal Investigator: Khashayar Sakhaee, M.D.
Summary: Kidney stones occur less commonly in women than in men. Compared with
men, women tend to have lower urinary calcium and higher urinary citrate (an
inhibition of calcium salt crystallizations). Among women with stones, the incidence
of stone formation has been reported to increase during fifth decade of life,
a time that corresponds to the onset of menopause in many women.
The objective of this study is to test the hypothesis that estrogen treatment
would attenuate the risk for the formation of calcium oxalate stones in early
postmenopausal women, but not in elderly women. The trial will test the hypothesis
that reported increase in stone formation rate during the fifth decade of life
in women is due to enhanced urinary calcium excretion from estrogen lack, and
that estrogen treatment would avert this complication.
III. Title of Project: Effect of Smoking and Smoking Cessation on Bone
Mineral Metabolism
Principal Investigator: Khashayar Sakhaee, M.D.
Summary: In human, genetically determined peak skeletal peak bone mass is generally
attained by 16 - 18 years of age, however, bone formation might continue into
third and fourth decades depending on the skeletal site, potentially allowing
for greater impact of environmental influences. Cigarette smoking has been suggested
to be environmental factor that might impair the attainment of peak bone mass
as well as accelerate bone mineral loss in later life.
This study would test the hypothesis that cigarette smoking results in increased
skeletal bone turnover might be mediated by alteration in vitamin D metabolism
leading to decreased intestinal calcium absorption and subsequent elevation
in PTH; and/or by decreasing estrogen levels, resulting directly in skeletal
bone turnover.
Finally, smoking cessation, results in a dose-dependent amelioration of the
above pathogenic mechanisms, leading to increased bone mineral density.
IV. Title of Project: Pathophysiology and molecular genetics basis of
gouty diathesis.
Principal Investigator: Khashayar Sakhaee, M.D.
Summary: Gouty diathesis is a clinical syndrome characterized by renal stone
formation in classic gout. Clinical patients present with kidney stones of uric
acid and/or calcium oxalate, and a low urinary pH of less than 5.5 without evidence
of confounding factors such as diarrhea or excessive acid intake. This study
would test the hypothesis that a defective renal ammonium production (a major
urinary buffer) exists and contribute to low urinary pH. Moreover, the patients
share many features of type-2 mellitus including obesity, dyslipidemia and hypertension.
Therefore, this project will also test a unifying hypothesis that insulin resistance
exists underlying the defective renal acidification, may ameliorate following
administration of insulin sensitizer.
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Principal Investigator: Howard Heller, M.D.
Each research student is exposed to both mineral metabolism and clinical research. You will go to pertinent clinics and conferences. You will be given lectures pertaining to mineral metabolism and clinical research. You will be assigned specific assignments in one of two projects below. Interested students will also be encouraged to be involved in the development of new protocols to experience the full spectrum of clinical research.
1. The Importance Of The Bone In Severe Absorptive Hypercalciuria
Absorptive hypercalciuria (AH), the most common cause of nephrolithiasis, results
from primary enhancement of intestinal calcium absorption. Interestingly, patients
with severe forms of the disease counterintuitively have low bone mass. Physiologic
explanation for the contradictory bone loss in the setting of excessive intestinal
calcium absorption has not been fully delineated.
The goal of this project is to better elucidate the pathophysiologic mechanisms
for bone loss and hypercalciuria in severe AH to allow formulation of more rational
treatment modalities. Each hypothesis below will be tested by comparing subjects
with well-characterized severe AH against matched normal volunteers and subjects
with immobilization hypercalciuria (ImH), a contrasting hypercalciuric condition
in characterized by excessive bone resorption and low intestinal calcium absorption.
All subjects will undergo bone biopsy and 2 provocative tests in a primarily
inpatient setting to test two main questions.
a. Is the bone loss primarily due to decreased bone formation or increased bone
resorption?
b. What degree does the bone contribute to the hypercalciuria?
This study has the potential to change the standard of care in hypercalciuric
patients.
2. What is the Molecular Cause of Absorptive Hypercalciuria?
In half of patients with AH, there is a family history of kidney stones. We
are involved in linkage studies with the goal of identifying genes that cause
kidney stones. The applicant will be involved in several aspects of research
including identifying families, scheduling and participating in the collection
of samples, and working in the lab with the samples.
3. Does Melatonin Lower Urinary Calcium? In animal studies, melatonin, which is available over-the-counter, increases bone mass and decreases bone resorption. Data supporting an effect of melatonin on mineral metabolism in humans is not available; however, one of our hypercalciuric stone-formers reproducibly decreased urinary calcium after self-treatment with melatonin for insomnia. In a subsequent pilot study, melatonin decreased urinary calcium in all six patients, but with sustained effect up to 5 months in only 2 subjects. We believe that the effect may be more sustained if the hepatic first phase effect, which destroys most of the melatonin, is bypassed with a sublingual preparation. In a new pilot study, hypercalciuric stone-formers will be tested before and after treatment with melatonin to answer these questions: a. Does melatonin lower urinary calcium? b. How (decreased intestinal calcium absorption, decreased mobilization of calcium from the bone, and/or improved renal calcium reabsorption).
4. Is Absorptive Hypercalciuria Caused by Impaired Upregulation of the Calcium
Sensing Receptor? The cause of intestinal calcium hyperabsorption in AH
is unclear. Observational studies have revealed high normal to elevated serum
1, 25-dihydroxyvitamin D (1,25-OHD) and low bone mass with decreased bone formation.
The calcium sensing receptor (CaSR), which is believed to be a fine regulator
of calcium in the serum and urine, is present in the parathyroid glands, kidney,
gut, and bone. With increasing serum calcium, the CaSR suppresses parathyroid
hormone secretion and renal calcium reabsorption, but its role in the gut and
bone is unknown. 1,25-OHD is known to upregulate CaSR expression, and vitamin
D response elements are present within the coding gene for CaSR. Therefore,
we hypothesize that AH may represent a subtle defect in calcium homeostasis
caused by impaired upregulation of CaSR expression in response to 1,25-OHD.
In a small pilot study, we will test the hypothesis by: a. Testing response
in calcium homeostasis (intestinal calcium absorption, bone turnover, renal
calcium reabsorption and calciotropic hormones) to the addition of 1000 mg of
calcium/day for 2 weeks. b. Testing the response in calcium homeostasis to 2
weeks treatment with Cinacalcet, which sensitizes the CaSR to calcium.