23.6: Calcium deficiency (23a.6)

23a.6.1 Hormonal responses to calcium deficiency

Calcium homeostasis is under systemic (i.e., hormonal) con­trol together with additional local regulating factors through intestinal absorption, influx and efflux from bone, and calcium excretion and re-absorption by the kidney. Serum calcium con­centrations must be kept con­stant at approximately 2.5mmol/L, a con­centration that is con­trolled by the interrelated action of three hormones: parathyroid hormone (PTH), 1,25(OH)₂D, and calcitonin. The first two hormones determine how much calcium is retained in the body through con­trol of absorption, bone turnover, and renal excretion. Calcitonin has a role in how calcium moves between the extra­cellular fluid and bone (EFSA, 2012).

Fasting, which represents acute calcium deficiency, causes a decrease in serum calcium con­centrations, inducing the release of PTH via the calcium-sensing receptor (CaSR) located on the cell surface of the parathyroid glands (EFSA, 2012). In hypo­calcemia, PTH has three actions which together bring serum calcium levels back to normal. The immediate response is bone resorption to release calcium into the blood. The second response is to increase renal re-absorption of calcium in kidney tubules in order to retain calcium. Finally, PTH stimulates 1,25(OH)₂D synthesis in the kidney (Figure 23a.1)

Figure 23a.1 Formation of vitamin D metabolites. Once the transport form 25(OH)D is made, the Endocrine pathway (Section 18b.2.4) for synthesis of the active metabolite 1,25(OH)₂D is illustrated. Parathyroid hormone (PTH) directs synthesis of 1,25(OH)₂D in response to a need for calcium or phosphate. Plasma 1,25(OH)₂D stimulates intestinal calcium transport and bone calcium mobilization, then blunts PTH synthesis to turn cycle off (Section 18b.13). Adapted from Holick, Kidney International 32: 912–929, 1987.

which serves to allow active absorption of calcium in enterocytes. Feedback con­trol of this rise in serum calcium occurs as a normal serum con­centration of calcium inhibits PTH secretion. In addition, higher than normal serum calcium stimulates calcitonin secretion by the para-follicular C cells of the thyroid gland, causing calcium to move into bone. Calcitonin's actual role in bone formation remains unclear, but it is a recognized treatment for hyper­calcemia (Felsenfeld and Levine, 2015).

23a.6.2 Bone health

Chronic calcium deficiency, arising from an habitually inadequate intake or poor absorption of calcium, is one of the many important factors associated with reduced bone mass. Bone mass in later life depends on the peak bone mass achieved during growth and the rate of the subsequent age-related bone loss. The age span over which peak bone mass is achieved is between the early teenage years and age 30, during which time 95% of bone mass is achieved. By 30y further gains are unlikely (Weaver et al., 2016), although exact timing varies with the skeletal site and sex. Optimization of bone mass is important because it reduces the risk of osteoporosis in later life.

Calcium intake and its association with bone health has been the subject of intense debate as epidemiological studies have not always found a con­sistent relationship between calcium intake and bone density. One reason is that calcium is a threshold nutrient so that when present in sufficient amounts, a higher calcium intake does not result in any further improvement in bone mineral accrual (Heaney, 2007). In most countries the Nutrient Reference Values (NRVs) have been set for main­tenance of bone health. For example, in the United States and Canada, the Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for calcium for all ages is based on main­taining a positive calcium balance in children and preventing a negative calcium balance in adults (IOM, 2011); more details are described below.

Calcium-deficiency rickets and osteomalacia occur in many parts of the world. Case reports from the United States, South Africa, and Nigeria have described infants and children with radiological rickets, growth retardation, and bio­chemical signs of hyper­parathyroidism but with normal vitamin D status. In all these cases of rickets, habitual calcium intakes were low but phosphorus intakes were adequate or high. Moreover, the children in South Africa responded to calcium-rich hospital diets (Thandrayon and Pettifor, 2018), whereas the Nigerian children responded more to calcium or a com­bination of calcium and vitamin D, and not to vitamin D alone (Thacher et al., 1999). Children with severe acute malnutrition experience hypo­calcemia and many have accompanying rickets (Smilie et al., 2020).

Osteopenia and osteoporosis are con­ditions characterized by a reduced bone mass. In osteopenia, the T‑score is low, at −1. In osteoporosis, reduction in bone mass is greater, i.e., the T‑score is −2 and there is increased bone fragility and risk of fracture. The T‑score is a relative rating expressed in standard deviation units describing the bone mineral density (BMD) measured at the spine, hip, or forearm. A T‑score is similar to a Z‑score except it is not measured against a same age person but rather against a young adult with normal BMD. Measurement is done using a variety of methods described in Section 23a.9. Osteoporosis diagnosis, according to the International Osteoporosis Foundation, (IOF), is done most often using BMD tests. For example, there is a Fracture Risk Assessment Tool for physicians to use with patients of both sexes called FRAX®. It is a web-based calculator to assess the ten-year risk of osteoporosis fracture based on specific individual risk factors, with or without BMD values (Kanis et al., 2018).There are separate country models for more than 60 individual countries, and it is available in more than 30 languages. The IOF supports the main­tenance, development, and education about the use of FRAX® worldwide. The factors used in FRAX® to predict 10y fracture risk are listed in Table 23a.4.

Table 23.4: Risk factors for osteoporosis used in the FRAX® Fracture Risk Assessment Tool for physicians to assess 10-year risk of developing osteoporosis. Source: www.iofbonehealth.org

Risk factors	Risk factors used in FRAX® to predict 10y fracture risk
Age	Increasing risk 40–90y
Sex	Female is risk factor
Weight and height	Low BMI is risk factor
Previous fracture	Previous fracture as adult is risk factor
Parent fractured hip	Indicates genetic risk
Smoking	Current use of tobacco is risk factor
Glucocorticoids	≥ 3mos prednisolone (≥ 5mg daily or equivalent) is a risk factor
Rheumatoid arthritis	Confirmed diagnosis of rheumatoid arthritis is a risk factor
Secondary causes of osteoporosis	Type I diabetes, adult osteogenesis imperfecta, untreated hyperthyroidism, hypogonadism or premature menopause, chronic malnutrition, malabsorption, chronic liver disease
Alcohol	≥ 3 or more units of alcohol daily is a risk factor
Bone mineral density (BMD)	Risk increases with decreased femoral neck BMD (in g/cm^2).

Dietary patterns and lifestyle factors such as sex, body composition, genetics, and physical activity con­tribute to bone health (Weaver et al., 2016). Dietary factors include high intakes of pro­tein and phosphorus (both as positive and negative influences) and suboptimal intakes of vitamin D as well as other micro­nutrients including vitamin K, vitamin C, magnesium, and zinc. These micro­nutrients are related to calcium metabolism and/or bone or con­nective tissue metabolism. However, based on a recent systematic review, the Level of Evidence was designated as “Inadequate Evidence” of the benefit of micro­nutrients (with the exception of calcium and vitamin D) on bone during acquisition of peak bone mass (Weaver et al., 2016). In examining dietary patterns, Moderate Evidence was found to support a beneficial role for dairy pro­ducts on bone, whereas for dietary fiber and fruit and vegetable intake the evidence on bone was deemed “Limited”. Likewise, the evidence for a detrimental effect of cola and caffeinated beverages on bone acquisition was also designated as “Limited”. For bone loss in older adults, a Canadian study con­cluded that the “Prudent” dietary pattern con­sisting of fruit, vegetables, whole grains, fish, and legumes reduced bone turnover com­pared to the Western diet of soft drinks, potato chips, french fries, meats, and desserts (Langsetmo et al., 2016).

23a.6.3 Non-bone effects of calcium deficiency

Calcium deficiency has been implicated in effects on health that are not bone-related. These include: reduction in hyper­tensive disorders of pregnancy, reduction in high blood pressure, reduction in risk of colorectal adenomas, and improvements in blood cholesterol in those at risk (Cormick and Belizan, 2019). Further, calcium has been implicated in weight management (Illich et al., 2009). The evidence for or against these effects is presented below. None of these non-bone effects were used to set Nutrient Reference Values (NRVs), yet each pro­vides additional reasons for being con­cerned about calcium adequacy. Blood pressure and calcium intake are inversely related in studies in humans as well as animal models, suggesting a role for calcium in main­taining normal blood pressure (Cormick and Belizan, 2019). Intracellular calcium regulates blood pressure in vascular smooth muscle cells, directly through vasocon­striction and indirectly through vascular volume con­trol (Villa-Etchegoyen et al., 2019). Hyper­tensive disorders of pregnancy, particularly eclampsia and pre-eclampsia, are a significant cause of severe morbidity, long-term disability and death among both mothers and their babies (WHO, 2018). Using moderate-certainty evidence from intervention studies, WHO has made the following recommendation: In populations with low dietary calcium intake, daily calcium supplementation (1.5–2.0g oral elemental calcium) is recommended for pregnant women to reduce the risk of pre-eclampsia. Additional con­siderations included in this recommendation are that all of the calcium may be from foods, if possible; that the intake should be obtained in divided doses, not all at once; and that iron supplements should be taken at a different time from calcium supplements.

Reduction in risk of colorectal adenomas with dietary calcium was first postulated in 1984, whereby in the presence of calcium ions, the toxic effects of free fatty acids on colon epithelial cells could be reduced by con­version to insoluble calcium soaps (Newmark et al., 1984). Since that time, numerous studies have refined this hypothesis, and pro­tective effects have been noted in animal studies. A systematic review and meta-analysis of randomized con­trolled trials regarding calcium supplementation for the prevention of colorectal adenomas found a modest pro­tective effect of calcium (1200–2000mg doses of supplemental calcium) in prevention of adenomas (Relative Risk (RR) = 0.89, 95% CI: 0.82–0.96) (Bonovas et al., 2016).

Blood cholesterol levels may be influenced by calcium intake. A systematic review reported that calcium supplementation reduced LDL cholesterol and increased HDL cholesterol through mechanisms involving suppression of calcium-regulating hormones (e.g., PTH) that subsequently reduced intracellular calcium in adipocytes, thus stimulating lipogenesis and lipid storage (Cormick and Belizan, 2019). However, as described below in Section 23a.7, excess calcium intake may be implicated in pro­moting cardio­vascular disease. Hence, to date there is no con­clusion regarding the role of calcium intake in reducing heart disease risk through cholesterol metabolism. Body weight con­trol by calcium has been debated for many decades. The initial suggestion arose from the finding that dairy intake facilitated weight loss better than low calorie diets without dairy, an effect that was attributed to calcium (Zemel et al., 2005). A recent trial com­pared the effect of supplements and dairy-con­taining foods and con­cluded that con­suming 4 to 5 servings of low-fat dairy foods per day or taking calcium and vitamin D supplements in persons with borderline dietary intakes of these two nutrients is beneficial for weight loss and/or main­tenance of weight loss in postmenopausal women (Ilich et al., 2009).