70.1

Introduction

Diet is an important modifiable risk factor for the prevention of osteoporosis. Studies have related several nutrients with bone health, such as vitamins A, B, C, D, E, K; minerals (potassium, magnesium, and silicon); and macronutrients (protein and fats) . Studies have also gone beyond single nutrient associations and linked foods, food groups, and dietary patterns with bone health. However, calcium and vitamin D are the primary nutrients considered for osteoporosis prevention and treatment in older adults.

Calcium is the most abundant mineral in the body contributing to critical functions related to vascular contraction, muscle function, nerve transmission, intracellular signaling, and hormonal secretion . Ninety-nine percent of the body’s calcium supply is stored in the bones and teeth where it supports structure and function. Bone acts as the calcium reservoir to maintain constant concentrations of calcium in the body. Vitamin D is a fat-soluble vitamin that is naturally occurring in very few foods. However, it is produced endogenously in the skin upon ultraviolet exposure. Biologically inert vitamin D, produced from sun exposure or obtained from diet or supplements, undergoes hydroxylation to convert to its active form, 1,25-hydroxy vitamin D or calcitriol. Vitamin D plays key roles in the body, including modulation of cell growth, neuromuscular and immune function, and the reduction of inflammation . It not only plays a role in bone growth and remodeling but also promotes calcium absorption in the gut and maintains adequate serum and phosphate concentrations for bone mineralization. With aging, there is a decline in calcium absorption and decline in serum 25-hydoxyvitamin D [25(OH)D] concentrations due to several reasons, which may in part increase the risk of age-related osteoporosis and consequent fractures in older adults. These adequate intakes of calcium and vitamin D are not only essential for osteoporosis prevention but also essential components of therapeutic treatments for osteoporosis. Although calcium and vitamin D have received significant attention, emerging evidence indicates that other nutrients also play an important role in skeletal health. The overview on nutrition and osteoporosis has been included in Chapter 21 , Nutrition and osteoporosis by Langsetmo et al., and nutrients beyond calcium and vitamin D are covered in Chapter 71 , Nutrients beyond calcium and vitamin D to treat osteoporosis by Nieves et al. The chapter discusses the interplay of calcium and vitamin D upon bone remodeling and reviews the data from human studies of calcium, vitamin D, and bone mineral density (BMD) and fractures. Finally, we also provide information on dietary recommendation of these two nutrients.

70.2

Bone remodeling, osteoporosis, and calcium

Calcium and vitamin D play key roles in bone health, which have been long supported by robust scientific evidence . Ninety-nine percent of the body’s calcium supply is stored in bone as mineral salt, a crystalline complex of calcium and phosphate called hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ). Hydroxyapatite crystals comprise 70% of calcified bone and are responsible for its rigidity . The relative ratio of calcium to phosphorus content in these mineral crystals varies depending on nutritional status. Osteoblasts, the bone forming cells, stimulate the deposition of mineral salts into the bone. Hydroxyapatite crystals are deposited along, and close to, each segment of collagen fiber, thereby preventing the collagen fibers from slipping out of place. Hydroxyapatite strengthens the tough organic matrix composed of collagen fibers, which provides bone with flexible strength, while hydroxyapatite provides compressional strength. On the other hand, osteoclasts play a key role in bone resorption by releasing proteolytic enzymes and acids to dissolve bone and release calcium into the blood .

As detailed in the previous chapter by Heaney , the skeleton is a metabolically active organ that undergoes continuous remodeling. Bone remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix through the osteoblasts that subsequently become mineralized . There are three stages of the remodeling cycle: resorption, reversal, and formation . Osteoclasts are responsible for the resorptive stage, followed by reversal by mononuclear cells on the bone surface and bone formation by osteoblasts. The whole process can take up to 4 months. Bone homeostasis is maintained by a balance between the action of osteoblasts and osteoclasts . A range of growth factors regulate the activity of osteoblasts. Receptors for these factors are found on osteoblasts along with receptors for classic hormones, such as parathyroid hormone (PTH), parathyroid-hormone–related protein, and thyroid hormone. Additional nuclear steroid hormones are found on osteoblasts, including receptors for estrogens, androgens, vitamin D3, and retinoids . Osteoclast activity is mediated by binding of integrins, expressed in osteoclasts, with proteins on the surface of bone matrix. Their function is regulated both by locally acting cytokines and by systemic hormones .

Calcium homeostasis refers to the hormonal regulation of serum ionized calcium by PTH, 1,25-dihydroxyvitamin D (1α,25(OH) ₂ ), and serum-ionized calcium itself, which together regulate calcium transport in the gut, kidney, and bone . Vitamin D and PTH act at three main sites to regulate extracellular calcium and phosphate: (1) small intestine, optimizing intestinal reabsorption of calcium; (2) kidneys, regulating renal excretion, and bone resorption independent of intestinal absorption; (3) bone, stimulating osteoblasts to produce a receptor called RANKL that ultimately stimulates osteoblasts to release calcium into the system ( Fig. 70.1 ) . Over time, increased PTH concentrations can lead to hypercalcemia and to significant bone loss, increasing the risk of fractures. PTH also stimulates resorption of phosphate from the bone but increases renal excretion of phosphate resulting in more phosphate excreted then resorbed. The net result of high PTH is that it decreases serum phosphate . Calcium absorption from dietary intake is dependent on several factors and only up to 30% of the calcium from food is actually absorbed . The efficiency of absorption is influenced by age, gender, vitamin D status and intake, other compounds present in food, and some medicines .

Vitamin D and PTH effect on calcium adapted from . Vitamin D and PTH act at three main sites to increase extracellular calcium: (A) small intestine—promotes absorption of calcium through the GI tract; (B) kidney—stimulates calcium reabsorption into the blood stream; (C) bone—stimulates calcium resorption. Note: all three sites have VDR receptors that bind vitamin D. Only the kidney and bone have PTHR receptors to bind PTH. PTH , Parathyroid hormone; VDR , vitamin D receptor.

70.3

Interplay of calcium and vitamin D

Calcium intake, along with adequate vitamin D status, is essential to maintain serum calcium within normal physiological concentrations . Vitamin D active metabolite mediates calcium absorption from the ileum in the gastrointestinal tract and is also involved in the regulation of calcium resorption from bone. Vitamin D increases the formation of calcium-binding proteins in the intestinal epithelial cells, which transport calcium through facilitated diffusion .

Vitamin D is the general term for two different molecules, ergocalciferol (vitamin D ₂ ) and cholecalciferol (vitamin D ₃ ). Vitamin D is a unique nutrient in that it can be photochemically produced in the skin as well as ingested through diet. Sunlight is considered the main source of vitamin D as up to 90% of the total acquired vitamin D can come from endogenous production. Casual exposure of the skin to ultraviolet B radiation converts the vitamin D precursor in the epidermis (7-dehydrocholesterol) to previtamin D ₃ , which quickly undergoes a thermal isomerization to become vitamin D ₃ . With aging the ability to form vitamin D through sunlight decreases significantly, and supplements may become necessary to maintain adequate concentrations . The ability to form vitamin D through exposure of the skin to sunlight is also influenced by the amount of melanin in the epidermis, which is responsible for skin pigmentation and acts as a filter to UV rays. Therefore individuals with darker skin might require greater exposure to sunlight in order to produce enough vitamin D .

Vitamin D from all sources (intake and endogenously synthesized) is transported in the circulation to the liver, to be converted to 25-hydroxyvitamin D, or 25(OH)D, which has a half-life of 2–3 weeks and is considered the best marker of vitamin nutritional status ( Fig. 70.1 ), but can be also stored in the liver for several months. The final conversion of 25(OH)D into 1α,25(OH) ₂ , its active form, occurs in the kidney’s proximal tubule. Vitamin D functions through a single vitamin D receptor. When serum calcium concentrations are low, calcium-sensing proteins found in the parathyroid gland stimulate the secretion of PTH, a potent bone-resorbing agent, in order to restore calcium normal concentrations . Only a very small amount (less than 0.03%) of the total vitamin D is free (in unbound form) .

70.4

Impact of calcium and vitamin D on bone mineral density

BMD is considered one of the main risk factors of fractures; hence, the correlation among calcium intake, vitamin D status, and BMD has been largely studied over the past decades . A considerable amount of human evidence supports the well-recognized and intuitive contribution of calcium for bone homeostasis maintenance and treatment strategies for osteoporosis. Human supplementation trials have also showed that higher calcium intake in the long-term could have relevant benefits to bone health and reduce the risk of osteoporosis by slowing the rate of bone loss associated with aging , and effects might be strongest in postmenopausal women, rather than perimenopausal (early stages) women . Observational studies as well as randomized controlled trials, as reviewed in the previous edition of this book , showed predominantly positive associations and effects of calcium and vitamin D supplementation on BMD and risk of fractures. In the following sections, we largely highlight studies published since the previous edition of this book.

70.4.2

Randomized controlled trials of bone mineral density and fracture

Several randomized controlled trials have investigated the effect of calcium and vitamin D supplementation on BMD. Calcium and vitamin D supplements have been generally found to positively affect BMD in older adults. Some trials have assessed the effects of calcium or vitamin D alone as the intervention, and some have investigated calcium and vitamin D together as a combined intervention. It is important to consider these two types of intervention separately in order to better understand and determinate to what extent the effects should be attributed to each nutrient or their combination.

Of the three classic studies on this topic, two showed benefit of calcium and vitamin D supplementation on bone, while one showed small benefit for BMD but none for fractures. A randomized control trial by Dawson-Hughes et al. published in 1997 is considered one of the pivotal trials in demonstrating the efficacy of calcium supplementation in the prevention and treatment of osteoporosis. In this RCT of men and women over 65 years of age ( n =389), dietary supplementation with either 500 mg calcium plus 700 IU of vitamin D per day or placebo, moderately reduced bone loss measured in the femoral neck, spine, and total body over the 3-year study period. This study further showed a significant reduction in the first nonvertebral fracture in the supplemented group (500 mg calcium plus 700 IU vitamin D, n of fractures=26) compared to the placebo ( n of fractures=11) over 3 years of follow-up [RR: 0.4 (95% CI: 0.2–1.0; P =.03)]. However, these findings should be interpreted with caution given the small sample size.

Similarly, Chapuy et al. demonstrated a significant protective effect of 1200 mg of calcium and 800 IU of vitamin D daily supplementation over 18 months in reducing fracture risk in 3270 French elderly (mean age 82±6 years) living in nursing homes . The calcium plus vitamin D supplementation group also showed an increase in BMD at the proximal femur by 2.7%. This study showed a remarkable reduction (43%) in hip fractures in the calcium plus vitamin D supplementation group compared to the placebo in women over 18 months. A more recent confirmatory 2-year RCT on the effects of the same combined dose of calcium and vitamin D supplementation in 610 French older women reported a decrease of femoral neck BMD, in the placebo group only, after 12 months of treatment , clearly showing a benefit of these two nutrients upon bone density. A difference between intervention groups was also seen for hip BMD. However, it is important to note that in this study, the placebo group presented very low baseline serum 25(OH)D concentrations (mean 13±9 ng/mL) and low calcium intakes (~500 mg/day as assessed by frequency questionnaire). Consistent with the current debate of the influence of initial 25(OH)D concentrations, this may imply that efficacy of these nutrients observed might not be extendable to populations with less significant deficiency.

The Women’s Health Initiative (WHI) trial, with 36,282 healthy postmenopausal women (aged 50–79 years), reported a small but significant higher hip BMD in the calcium (1000 mg) plus vitamin D (400 IU) group compared to the placebo group over 7 years of follow-up, although no significant reduction in hip fracture, spine fracture, or total fractures was observed in this study . Some of this dilution of effect could be attributed to the lack of adherence and use of personal supplements by the study participants because sensitivity analysis to assess effect of nonadherence by censoring data from women who ceased to adhere to the study medication showed a significant reduction in hip fracture by 29% in the treatment group compared to the placebo group. This suggests that although calcium and vitamin D supplementation may be efficacious, it is likely to be more effective in older postmenopausal women over the age of 60 years at risk of fractures. However, authors also reported an increased risk of self-reported kidney stones in this study. It is important to note that in this population the average calcium intake was ~1150 mg/day and vitamin D serum concentrations around 46 nmol/L. The outcomes observed in this study may be due to the relatively high baseline vitamin D concentrations or the unsatisfactory compliance to treatment from participants reported by the study or variations on vitamin D baseline status. Subsequent analysis of WHI data further reported on fracture outcomes 4.9 years after the intervention stopped. Over an average of 11 years of follow-up, there was a 13% reduction in the risk of vertebral fractures among supplement users . Similarly, another study analyzed WHI data to examine long-term use of calcium and vitamin D supplements with an emphasis on fractures. Among women not taking personal calcium or vitamin D supplements at baseline, long-term calcium and vitamin D supplement use (≥5 years) was associated with 38% reduction in hip fracture risk compared with placebo group (RR: 0.62; 95% CI: 0.38–1.00). When this data was combined with WHI prospective observational study, there was a 35% reduction in hip fracture risk (RR: 0.65; 95% CI: 0.44–0.98) .

As outlined in Table 70.2 and discussed next, recent RCTs have further investigated the effect of both calcium and vitamin D ₃ supplementation, either combined or not, in older populations.

Table 70.2

Calcium and vitamin D supplementation and bone mineral density (BMD): randomized controlled trials (2012–18).

Reference	Population	Duration (months)	n	Age (years)	Vitamin D dose (IU/day)	Ca dose (mg/day)	Results
Calcium
Nakamura et al.	Healthy women	24	450	50–75	–	500 or 250 mg of calcium or placebo	↓Lumbar spine BMD loss in supplemented groups relative to placebo ↓Femoral neck BMD loss in 500 mg/day group relative to placebo
Rajatanavin et al.	Postmenopausal women	24	404	>60	–	500 mg or placebo	↑Lumbar spine BMD increased in supplement group alone, but no significant change in placebo group Femoral neck BMD had no change in supplemented group, but significant decrease in placebo group
Vitamin D
Hansen et al.	Postmenopausal women	12	221	60–75	800 IU daily or 50,000 IU twice monthly or placebo	–	No association
Reid et al.	Elderly ( ViDA study)	24	452	50–84	100,000 IU monthly or placebo	–	Significant attenuation of bone loss in hip sites by about 0.5% over 2 years in supplemented group No significant treatment effect in lumbar spine and decline in proximal femur and total body for both groups
MacDonald et al.	Postmenopausal women (The Aberdeen Study)	12	305	60–70	400 IU; 1000 IU or placebo	–	BMD loss at the hip reduced in the high-dose group only Significant treatment effects apparent at the spine and hip for baseline 25(OH)D ≤12 ng/mL only
Calcium plus vitamin D
Rahme et al.	Healthy elderly	12	257	>65	3750 or 600 IU	1000 mg (both groups)	No significant differences in change BMD between the groups at any skeletal site. Compared to baseline, significant increments in percent change BMD at total hip and lumbar spine in both groups. No between groups change in BMD at any skeletal site.
Pop et al.	Postmenopausal women	12	81	50–70	600, 2000, or 4000 IU	1200 mg (all groups)	Decrease in cortical thickness in the lower dose group but not in the higher doses
Smith et al.	Healthy women	12	194	57–90	400, 800, 1600, 2400, 3200, 4000, or 4800 IU/day or placebo	To total calcium intake of ~1200 mg/day	No significant effect of daily vitamin D doses ranging from 400 to 4800 IU/day on BMD in older women who started with low serum 25(OH)D <50 nmol/L

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