Lactation Clinical Trial
Official title:
A Prospective Cohort Pilot Study of Bone Metabolism in Lactating and Non-lactating Postpartum African-American Women and Healthy Non-pregnant African-American Women
The primary aim of this study is to obtain measures of amino-terminal telopeptides of
procollagen 1 (P1NP), a marker of bone formation, in lactating and non-lactating post-partum
African-American women both at 6-8 and at 12-14 weeks post-partum, and to compare these
values to those of normal controls. The secondary aim is to obtain at the same time points,
measurements of Parathyroid Hormone-related Protein (PTHrP), additional markers of bone
turnover [e.g. N-telopeptide of collagen cross-links (NTx), C-telopeptide of collagen
cross-links (Ctx),bone specific alkaline phosphatase (BSAP) and osteocalcin (OC)], calcium
and vitamin D metabolism in these subjects. These results will be compared with a
non-African-American cohort of post-partum women and normal controls.
The investigators hypothesize that African-American lactating women will have increased bone
turnover when compared to non-lactating postpartum women and normal controls. The
investigators further hypothesize that bone turnover is increased in lactating women
independent of race.
Pregnancy and lactation are both states of altered maternal calcium and bone metabolism
which may have a significant impact on the development of peak bone mass. While these two
states are characterized by different hormonal environments, both have been associated with
significant bone loss. The maternal hormonal mechanism for providing calcium to meet the
needs of the developing fetus appear different from those that meet the needs of lactation.
During pregnancy, the 30 gm of calcium required by the fetus comes predominantly from an
increase in maternal intestinal calcium absorption which is mediated by 1,25 dihydroxy
vitamin D and other factors. Several studies have measured total and free 1,25 dihydroxy
vitamin D through pregnancy and find the values nearly double. Serum Parathyroid Hormone
(PTH) levels fall to about 10-30% of the mean non-pregnant value in the first trimester and
then increase to the mid-normal range by term, while ionized calcium remains normal
throughout pregnancy. Parathyroid Hormone-related Protein (PTHrP) levels gradually increase
throughout pregnancy although the source (maternal, fetal, or placental) remains unclear.
Most studies of bone metabolism in humans during pregnancy have measured changes in markers
of bone turnover rather than bone density to avoid radiation exposure to the fetus. These
studies have been confounded by several variables such as the effects of hemodilution in
pregnancy, altered glomerular filtration rates (GFR), degradation and clearance of markers
by the placenta, which may cloud the results. Some of these studies report an increase in
urinary markers of bone resorption from early to mid pregnancy while bone formation markers
decrease and then rise before term. Importantly, no one has assessed state-of-the-art
markers of bone formation such as type 1 Procollagen N-terminal Propeptide (P1NP) in
pregnancy or lactation.
During lactation in humans, it is estimated that 600 to 1000 ml of milk are produced a day
with daily calcium loss of 200 to 400 mg. In contrast to pregnancy, a majority of this
calcium comes from demineralization of the maternal skeleton, and is probably predominately
mediated by PTHrP in the setting of low estrogen. PTHrP levels are significantly higher in
lactating women than non-lactating controls while intact PTH is reduced by approximately 50%
during the first several months of lactation. The source of the PTHrP is likely the mammary
gland, as PTHrP levels are elevated 10,000 fold in milk and circulating maternal PTHrP
levels are increased further with suckling. This is also supported by a mouse model in which
the tissue-specific ablation of the PTHrP gene in the lactating mammary gland resulted is a
decrease in bone loss during lactation. When PTHrP enters the maternal circulation, it
stimulates maternal bone resorption from the skeleton and renal tubular resorption of
calcium. PTHrP indirectly suppresses PTH as ionized calcium rises to upper levels of normal.
1,25 dihydroxyvitamin D levels fall to within the normal range during lactation, although
they have been reported to be higher in lactating than non-lactating postpartum women.
Intestinal absorption of calcium also returns to normal during the post-partum period.
Serial bone density measurement (BMD)obtained during lactation show a fall of 3-10% in
trabecular bone (spine, hip, femur) with a smaller 1-2% loss at cortical bone. Both losses
are far greater that than that seen in early postmenopausal women, or in women receiving
gonadotropin releasing hormone (GnRH) agonist therapy. This implies that it is not only the
fall in estrogen that mediates bone loss during lactation. The bone loss during lactation
seems to be transient as there is rapid recovery of bone density in postpartum women with
weaning and the resumption of menses.
Markers of bone resorption have been measured in urine in several prospective studies of
lactation in humans where they have been reported to be elevated 2-3 fold. However, these
results may be confounded by a decrease in GFR and volume contraction that may occur during
lactation compared to pregnancy. Surprisingly, more reliable markers of bone resorption
measured in serum (CTX and NTX) have not been measured in a controlled lactation study.
Markers of bone formation as measured by osteocalcin (Oc) and bone specific alkaline
phosphatase (BSAP) have generally been reported to be higher during lactation. However,
these results are difficult to interpret as BSAP is not a very sensitive marker of bone
formation. Recent data has emerged suggesting that Oc may measure bone resorption as well as
formation. The current most accurate measure of bone formation is serum amino-terminal
telopeptides of procollagen 1 (P1NP), which until recently had not been measured in a
control study of lactating women. We are currently analyzing data from a controlled study of
lactation in Caucasian, Hispanic, and Asian women.
Most of the studies on bone metabolism during pregnancy and lactation have been performed in
Caucasian females. Most studies have excluded African-Americans due to the unique
differences in bone metabolism known to occur in this population which may create wider
statistical variation in the study results.
It is well established that bone metabolism in African American subjects differs from the
Caucasians in several aspects. The mean 25-hydroxyvitamin D levels are lower in
African-Americans primarily due to reduced vitamin D production in the skin associated with
increased pigmentation as well as reduced intake of vitamin D. As a consequence,
African-Americans have relative secondary hyperparathyroidism and resultant higher levels of
PTH, and 1, 25 dihydroxyvitamin D, and lower urinary calcium excretion. One would expect
that patients with secondary hyperparathyroidism would result in increased bone turnover and
decreased bone mass. This is not what is observed in African Americans though. African
Americans have higher bone density and lower fracture risk as compared to Caucasians.
Moreover, biochemical markers of bone turnover in African-Americans are in general lower
than in Caucasians, particularly for bone formation, as measured by osteocalcin. On the
other hand, there is normal or increased renal absorption of calcium. Based on these, Dr.
Normal Bell proposed that the black skeleton is resistant to the effects of PTH, while renal
sensitivity is maintained or even enhanced. This hypothesis is further supported by the
observation of significantly lower bone resorption (as measured by cross-linked
N-telopeptide of procollagen I (NTx), cross-linked C-telopeptide of type I collagen (CTx),
and free deoxypyridinoline (DPD) and normal to low renal excretion of calcium in response to
PTH infusion in African American as compared with Caucasian women.
This is a prospective cohort study of post-partum lactating, non-lactating, and healthy
control African-American women who are not currently or have not recently been pregnant. The
investigators hope to estimate the measurable differences in bone formation and resorption
by comparing blood and urine samples from African-American lactating women to
African-American non-lactating postpartum women and normal controls. 100 female volunteers
between the ages of 21-45 years will be recruited to achieve 75 evaluable subjects or 25 in
each of the three groups. There are two out-patient visits, each 6-8 weeks apart. The visits
will take place at the University of Pittsburgh Medical Center (UPMC) - Clinical &
Translational Research Center (CTRC) located on 6 North East (6 NE) in Montefiore Hospital.
The post-partum subjects will be recruited during their last trimester of pregnancy or at
their 6-week post-partum visit. Healthy controls will be recruited and matched to a
breast-feeding postpartum woman who has already completed the study. Visit 1 for all
postpartum women will take place at 6-8 weeks after delivery and Visit 2 at 14 weeks after
delivery. Healthy control subjects will have two study visits at similar intervals to their
matched breast-feeding subject (1.5 to 2 months). For all subjects, an informed consent will
be obtained at the first visit, before any study procedures are done: including a medical
history and measurement of vital signs, an intake history about menstrual cycles, pregnancy,
and if applicable, delivery and breast or bottle feeding events. Subjects will complete a
dietary calcium intake questionnaire. Blood collections are obtained at each visit for
measurements of the following: serum ionized and total calcium, phosphorus, creatinine,
albumin, PTH(1-34), PTH(1-84), PTHrP (1-36), 25-hydroxy Vitamin D by High Performance Liquid
Chromatography (HPLC), including D2 and D3, 1,25 (OH)2 vitamin D, estrogen status,
Luteinizing Hormone (LH), Follicle-stimulating Hormone (FSH), Estradiol, and markers of bone
metabolism (e.g. NTX, CTX, P1NP, Osteocalcin (OC), BSAP, Insulin-like growth factor-1
(IGF-1), and selected cytokines of the interleukin-6 (IL-6). Urine samples will be obtained
for calcium, creatinine and phosphorus. A urine pregnancy test will be done at each visit
for normal controls. Post-partum women will have a urine pregnancy checked at Visit 2 only,
to avoid false positives that are likely at Visit 1 due to the recently completed pregnancy.
Thyroid Stimulating Hormone (TSH) will be checked at Visit 1 to exclude those women who have
significant alterations in thyroid functioning that could interfere with bone metabolism.
;
Observational Model: Cohort, Time Perspective: Prospective
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT02542527 -
Evaluation of the Functionality of a Fluid Filled Single Breast Pump
|
N/A | |
Terminated |
NCT02755194 -
"Drugs in Lactation" Analysis Consortium
|
||
Terminated |
NCT00851591 -
Effect of Fenugreek on Milk Production
|
N/A | |
Withdrawn |
NCT00181649 -
Recombinant Human Prolactin for Lactation Induction
|
Phase 2 | |
Completed |
NCT00181610 -
Recombinant Human Prolactin for Lactation Induction
|
Phase 2 | |
Completed |
NCT04024865 -
Domperidone and Risk of Serious Cardiac Events in Postpartum Women
|
||
Terminated |
NCT02378233 -
Iodine Status in Swedish Lactating Women - Effect of Iodine Supplementation in the Thyroid Function of Mother and Infant
|
N/A | |
Recruiting |
NCT06203444 -
An Open-label Study to Evaluate the Pharmacokinetics of Oral Tenapanor in Breast Milk of Lactating Females
|
Phase 1 | |
Completed |
NCT01747668 -
Lactation Fortification Study
|
Phase 3 | |
Completed |
NCT01463202 -
Timing of Postpartum Depot Medroxyprogesterone Acetate Administration on Breastfeeding, Contraceptive Continuation, and Depression
|
Phase 4 | |
Completed |
NCT02621827 -
Vitamin D Half-life in Pregnancy and Lactation
|
N/A | |
Terminated |
NCT04146909 -
The Effect of Lactation on Insulin Sensitivity and Lipolysis in Women
|
N/A | |
Completed |
NCT04593719 -
Effect of Lactation Management Model on Breastfeeding Process
|
N/A | |
Completed |
NCT01548313 -
The Role of Human Milk in Development of Breast Fed Child's Intestinal Microbiota
|
||
Completed |
NCT02690675 -
Iron Supplement Effect on Child Development
|
N/A | |
Completed |
NCT05123183 -
Nonpharmacological Methods and Lactation
|
N/A | |
Completed |
NCT03091985 -
Influence of the Brownie Breast Shield on the Dynamics of Milk Removal
|
N/A | |
Completed |
NCT02190448 -
Randomized, Placebo-Controlled Study of an Herbal Tea to Support Lactation
|
N/A | |
Not yet recruiting |
NCT06264349 -
Women and Maternity: Development of a Nutritional Education Project
|
N/A | |
Recruiting |
NCT02384655 -
Effect of Fenugreek Use in Mothers of Preterm on Breast Milk Production and Macronutrient Content
|
Phase 1/Phase 2 |