Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India.
Division of Endocrinology and Centre for ASTHI, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
Bone. 2020 Dec;141:115562. doi: 10.1016/j.bone.2020.115562. Epub 2020 Jul 28.
Calcipenic rickets is prevalent in underprivileged children in developing countries. Calcipenic rickets resulting from dietary calcium (Ca) deficiency decreases bone mass and deteriorates bone microstructure in humans. The effect of dietary Ca replenishment (CaR) on rachitic bones in animal models depends on the amount, critical period and duration of replenishment, however, the extent of recovery in various bone parameters including bone quality remains unclear. We investigated the effect of CaR in rat skeleton after inducing calcipenic rickets. Female SD rats (postnatal 28 days/P28) were rendered calcipenic by feeding calcium deficient (CaD) diet (0.1% Ca) till P70 while control SD rats were fed Ca sufficient diet (0.8% Ca). At P70, calcipenic rats were switched to 0.8% Ca diet till P150 for one group and P210 for another group (endpoint). The CaD groups received 0.1% Ca diet throughout the study (P210). In the CaD groups, serum Ca and phosphate, and bone mineral density (BMD) were significantly decreased whereas serum alkaline phosphatase (ALP), iPTH and CTX-1 were increased compared to age-matched controls. Moreover, at the endpoint, the CaD group had reduced bone mass, surface referent bone formation parameters, tissue mineralization and strength accompanied by the increased osteoid thickness and microarchitectural decay (measured by trabecular geometric parameters) with poor crystal packing. The CaR group showed complete recovery in serum Ca, iPTH, ALP and CTX-1, and BMD, however, the bone quality parameters including bone strength, microarchitectural decay, tissue mineralization, and crystallinity were incompletely restored. Decreased surface referent bone formation and increased unmineralized bones (osteoid) indicative of osteomalacia were also observed in the CaR group at P210 compared with control despite prolonged replenishment. We conclude that a prolonged Ca repletion following the induction of calcipenic rickets in rats although shows the recovery of biochemical measures of bone metabolism and bone mass, however, the bone quality remains compromised. This suggests that a "memory" of calcipenia occurring at the early growth stage persists in the skeleton of adult rats despite a prolonged Ca replenishment.
低钙性佝偻病在发展中国家贫困儿童中较为普遍。由于饮食中钙（Ca）缺乏而导致的低钙性佝偻病会降低人体的骨量并使骨微观结构恶化。饮食中补充 Ca（CaR）对动物模型中佝偻病骨骼的影响取决于补充的量、关键时期和持续时间，然而，各种骨参数（包括骨质量）的恢复程度仍不清楚。我们研究了在诱导低钙性佝偻病后，大鼠骨骼 CaR 的作用。雌性 SD 大鼠（出生后 28 天/P28）在 P70 前通过喂养低钙（CaD）饮食（0.1% Ca）使其成为低钙性佝偻病，而对照 SD 大鼠则喂养足够 Ca 的饮食（0.8% Ca）。在 P70 时，低钙性佝偻病大鼠转换为 0.8% Ca 饮食，一组直至 P150，另一组直至 P210（终点）。CaD 组在整个研究过程中都接受 0.1% Ca 饮食（P210）。在 CaD 组中，血清 Ca 和磷酸盐以及骨矿物质密度（BMD）显著降低，而血清碱性磷酸酶（ALP）、iPTH 和 CTX-1 则与年龄匹配的对照组相比升高。此外，在终点时，CaD 组的骨量、表面参照骨形成参数、组织矿化和强度降低，同时伴有骨矿化率增加和微结构恶化（通过小梁几何参数测量），伴有较差的晶体排列。CaR 组血清 Ca、iPTH、ALP 和 CTX-1 以及 BMD 完全恢复，但包括骨强度、微结构恶化、组织矿化和结晶度在内的骨质量参数并未完全恢复。尽管补充时间延长，但与对照组相比，CaR 组在 P210 时仍观察到表面参照骨形成减少和未矿化骨（类骨质）增加，提示佝偻病发生的“记忆”在大鼠成年骨骼中持续存在，尽管补充时间延长。我们得出结论，在大鼠中诱导低钙性佝偻病后，长期补充 Ca 虽然恢复了骨代谢和骨量的生化指标，但骨质量仍然受损。这表明，尽管长期补充 Ca，但在早期生长阶段发生的低钙血症“记忆”在成年大鼠的骨骼中持续存在。
