Longitudinal Lactation Bone Density Study
Condition: Lactation; Other Disorders of Bone Density and Structure; Endocrine; Complications
MeSH terms: Bone Diseases
Study type: Observational

Summary: 
      Changes in maternal calcium metabolism are necessary during lactation to provide adequate
      calcium in breast milk for development of the newborn skeleton. The calcium in milk is
      derived from the maternal skeleton, resulting in significant bone loss, a process thought to
      be mediated by the actions of parathyroid hormone-related protein (PTHrP) in combination with
      a decreased estrogen levels. After weaning, bone lost during lactation is rapidly regained.

      Differences between African-American and Caucasian bone metabolism are well documented and
      include higher bone mineral density (BMD), lower risk of fragility fracture, lower
      25-hydroxyvitamin D (25(OH) D), and higher PTH in African-Americans compared to Caucasians.
      Most studies of bone metabolism in lactating women have been done in Caucasians. Because of
      differences in bone metabolism between African-Americans and Caucasians, we do not know
      whether African-Americans will have similar findings.

      The primary aim of this study is to compare the changes in bone mineral density (BMD) during
      lactation in African-Americans with those in Caucasians. It is not known whether the loss in
      BMD during lactation will be the same for both races. African-Americans display skeletal
      resistance to PTH with short-term infusions and have lower bone resorption, higher BMD and
      lower fracture risk than Caucasians. A recent study by our group indicated that lactating
      African-American mothers had slightly lower bone resorption but quantitatively similar bone
      formation compared to Caucasians. However, there was a significant increase of 2-3 fold in
      markers of bone formation and resorption in both groups. Therefore, it is currently not known
      whether the loss in BMD during lactation will be the same for both races. Primary outcome
      measures in this study will include spine, hip and radius BMD by Dual X-Ray Absorbiometry
      (DXA)Scans during lactation (at 2,12 and 24 weeks postpartum or at weaning if prior to 24
      weeks postpartum, and six months after weaning (+1 week). This longitudinal protocol will
      distinguish between two hypotheses. Either: a) as measured by BMD, bone loss in
      African-Americans during lactation will be equal to that in Caucasians, and skeletal recovery
      will be the same or possibly accelerated compared to Caucasians; or, b) African-Americans
      will be resistant to bone loss during lactation compared to Caucasians because of resistance
      to Parathyroid Hormone-related Protein (PTHrP).
    

Detailed description: 
      Pregnancy and lactation are both states of altered maternal calcium metabolism. Maternal
      calcium mobilization is essential in the provision of an adequate calcium supply to the
      developing fetus and infant. During pregnancy approximately 30 grams of calcium is required
      for fetal skeletal development. The extra calcium is derived mostly from increased maternal
      intestinal absorption, mediated by 1,25 dihydroxyvitamin D (1). During lactation, it is
      estimated that 600-1000 ml of milk are produced daily with a net maternal calcium loss of
      200-400 mg per day (2,3). This calcium is derived from the maternal skeleton, resulting in
      bone loss of as much as 10% of trabecular bone with serial bone density measurements (3).
      Demineralization is thought to be mediated predominantly by the actions of parathyroid
      hormone-related protein (PTHrP) in combination with a suppressed estrogen state.
      Interestingly, this state rapidly reverses itself with weaning (4,5). Several studies have
      shown that initial PTHrP measurements are significantly higher in lactating women(3). PTHrP
      in lactation is produced in high amounts by the mammary gland. Once in the circulation, PTHrP
      increases bone resorption from the maternal skeleton and increases calcium resorption at the
      level of the kidney (5,6,27). PTHrP levels have been found to be elevated as much as 10,000
      fold in milk as compared with maternal serum, and further increase with suckling (1,6,28). In
      mouse models, tissue specific-ablation of the PTHrP gene in lactating mammary gland results
      in decreased bone loss(6).

      Given the rapid bone loss reported in lactation, an increase in markers of bone resorption
      and a decrease in markers of bone formation might be expected. However, a recently published
      study by our group showed that both markers of bone formation and bone resorption were
      significantly elevated in lactating Caucasian women (7). This seems unlikely as tight
      coupling of bone formation and resorption would not result in net calcium mobilization and
      rapid bone loss during lactation. A more likely explanation is that while bone resorption
      markers accurately reflect robust osteoclastic bone resorption, the increase in markers of
      bone formation reflects an increase in immature, partially differentiated pre-osteoblasts
      that are arrested in development and therefore unable to effectively form new bone. Thus, the
      rate of resorption exceeds that of formation during lactation and results in a temporary net
      loss. To support this idea, rat studies have shown that continuous exposure to PTH and PTHrP
      recruits and initiates osteoblast differentiation, but stops the program prematurely at the
      preosteoblast transition (8,9,10). This would also suggest a mechanism for the rapid recovery
      seen after weaning: after withdrawing the PTHrP stimulus, osteoclast-mediated bone resorption
      would abruptly cease, and previously recruited osteoblast precursors would rapidly complete
      their differentiation program and restore bone lost during lactation.

      African-American bone metabolism differs from Caucasian bone metabolism in several ways.
      African-Americans display higher bone density and are at lower risk of developing
      osteoporosis and osteoporotic fracture compared to Caucasians (15-17,29-31). There are may
      factors which may explain these racial differences in bone metabolism, including altered
      calcium economy, vitamin D differences, peak attained bone mass, muscle mass and obesity,
      remodeling rates, bone micro-architecture, hip axis geometry , and other unknown hereditary
      differences. In particular, it is well established that 25-Hydroxyvitamin D (25-OH D) levels
      are much lower in African-Americans, due to darker pigmentation resulting in reduced dermal
      production of 25-OH D as well as reduced intake of vitamin D (11). This hypovitaminosis
      results in a relative secondary hyperparathyroidism, corroborated by higher levels of PTH and
      1,25 dihydroxyvitamin D as well as decreased urinary calcium excretion (12-14).
      Paradoxically, these higher PTH levels do not correlate with an increase in bone loss. In
      fact, bone turnover is actually reduced compared to Caucasians, suggesting that
      African-American bones are more resistant to the effects of PTH, whereas renal sensitivity is
      maintained or increased (14,18).

      The vast majority of studies examining bone metabolism in lactating women have been in
      Caucasian women. Studies on bone turnover and calcitropic hormones in lactating
      African-Americans are scarce. Over ten years ago, a study examined markers of bone metabolism
      in a population of lactating Gambian women (in Gambia) and compared them with a similar
      cohort of British lactating women (in the UK). The study demonstrated significant increases
      in older markers of bone formation and resorption during lactation, but also showed higher
      levels of PTH, 1,25 Vitamin D, serum phosphate, osteocalcin, and alkaline phosphatase in the
      Gambian lactating population compared with the British lactating population (19). However,
      Gambian women differ significantly from black women in the developed world in terms of
      nutrition, both overall calories and calcium intake. Also in contrast to African-Americans,
      black Gambian women displayed lower BMD than Caucasians. Interestingly, in these studies,
      Gambian women demonstrated significant losses in whole body and hip BMD during lactation and
      showed little evidence of bone mass regain after weaning. In fact, Gambian women had
      continued BMD loss at the hip, in contrast to Caucasian controls.

      A recent study by our group (unpublished) explored bone turnover markers and calcium
      metabolism in African-American lactation. Markers of bone resorption were lower in
      African-American than Caucasians in non-lactating young women, but increased 2-3 fold in both
      groups during lactation. Baseline bone formation was comparable in African-Americans and
      Caucasians, also increasing 2-3 fold in both groups. Fractional excretion of calcium was
      lower in African-Americans at baseline and remained constant in both groups during lactation.
      It remains unclear whether bone loss occurs at a similar rate during lactation in the
      African-American population.

      Up to this point, there have been no studies in African-Americans that have utilized bone
      densitometry to quantitate bone loss and recovery during lactation. This study aims to
      demonstrate changes in bone density in African-American women during the high bone turnover
      state of lactation. It will also permit measurements of calcium metabolism, markers of bone
      formation and resorption, and calcitropic hormones to be compared to bone density changes. We
      will also look for racial differences in lactating bone metabolism by directly comparing a
      cohort of African-American lactating women with a similar Caucasian cohort. No prior studies
      have been done comparing bone mineral density changes in lactating American black and
      Caucasian women.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        New mothers will be recruited from UPMC hospital population, primarily Magee Womens
        Hospital. As this is a study which aims to describe racial differences in bone metabolism
        during lactation in African-Americans and Caucasians, subjects must identify themselves as
        belonging to one of these groups.
      
Biospecimen description: 
      Blood and breast milk
    
Keywords: Lactation; Weaning; Bone Density; Endocrine; Physiological Properties; Bone Metabolism