Bone Metabolism and Parathyroid Hormone-related Protein (PTHrP) Lactation Study
Condition: Bone Diseases, Endocrine
MeSH terms: Bone Diseases; Bone Diseases, Endocrine; Endocrine System Diseases
Study type: Observational

Summary: 
      The primary aim of the study is to measure bone formation in both lactating and non-lactating
      post-partum women and compare these to those in healthy non-pregnant controls. The secondary
      aim is to obtain measurements of Parathyroid Hormone-related Protein (PTHrP), markers of bone
      resorption, and calcium and vitamin D metabolism in these subjects. The investigators believe
      that lactating women will have an increase in bone resorption but no increase in bone
      formation when compared to non-lactating post-partum women and normal controls.
    

Detailed description: 
      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 to differ 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. 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 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 dihydroxy vitamin 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 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 has not been measured in a control study of lactating women.

      This is a prospective pilot cohort study of post-partum lactating women, post-partum
      non-lactating women, and matched healthy controls 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 lactating women to
      non-lactating postpartum women and normal controls. 100 female volunteers between the ages of
      21 and 45 years will be recruited to achieve 75 evaluable subjects or 25 in each of the three
      groups. There are two study visits, one at 6-8 weeks and another at 12-14 weeks postpartum.
      Normal controls will be seen during the follicular phase of their menstrual cycle and they
      will be age and race matched to the post-partum women.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        New mothers who are either almost exclusively breast feeding or bottle feeding; normal
        controls to match those new mothers.
      
Biospecimen description: 
      archival blood serum and plasma
    
Keywords: Pregnancy; Lactation; Endocrine System Diseases; MusculoSkeletal System Disease; Hormone; Physiologic Properties