SPECIFIC DISORDERS INVOLVING BONE MINERAL-REGULATING HORMONES
This rather common disease, if associated with symptoms and significant hypercalcemia, is best treated surgically. Oral phos-phate and bisphosphonates have been tried but cannot be recom-mended. Asymptomatic patients with mild disease often do not get worse and may be left untreated. The calcimimetic agent cinacalcet, discussed previously, has been approved for secondaryhyperparathyroidism and is in clinical trials for the treatment of primary hyperparathyroidism. If such drugs prove efficacious and cost effective, medical management of this disease will need to be reconsidered.
In PTH deficiency (idiopathic or surgical hypoparathyroidism) or an abnormal target tissue response to PTH (pseudohypopara-thyroidism), serum calcium falls and serum phosphate rises. In such patients, 1,25(OH)2D levels are usually low, presumably reflecting the lack of stimulation by PTH of 1,25(OH)2D pro-duction. The skeletons of patients with idiopathic or surgical hypoparathyroidism are normal except for a slow turnover rate. A number of patients with pseudohypoparathyroidism appear to have osteitis fibrosa, suggesting that the normal or high PTH levels found in such patients are capable of acting on bone but not on the kidney. The distinction between pseudohypoparathy-roidism and idiopathic hypoparathyroidism is made on the basis of normal or high PTH levels but deficient renal response (ie, diminished excretion of cAMP or phosphate) in patients with pseudohypoparathyroidism.
The principal therapeutic concern is to restore normocalcemia and normophosphatemia. Vitamin D (25,000–100,000 units three times per week) and dietary calcium supplements have been used in the past. More rapid increments in serum calcium can be achieved with calcitriol. Many patients treated with vitamin D experience episodes of hypercalcemia. This complication is more rapidly reversible with cessation of therapy using calcitriol than therapy with vitamin D. This would be of importance to the patient in whom such hypercalcemic crises are common. Although teriparatide (PTH 1-34) is not approved for the treatment of hypoparathyroidism, it can be quite effective in patients who respond poorly to calcium and vitamin D and may become the drug of choice for this condition.
The level of vitamin D thought to be necessary for good health is being reexamined with the appreciation that vitamin D acts on a large number of cell types beyond those responsible for bone and mineral metabolism. A level of 25(OH)D above 10 ng/mL is necessary for preventing rickets or osteomalacia. However, substantial epidemiologic and some prospective trial data indicate that a higher level, such as 30 ng/mL, is required to optimize intestinal calcium absorption, optimize the accrual and mainte-nance of bone mass, reduce falls and fractures, and prevent a wide variety of diseases including diabetes mellitus, hyperparathyroid-ism, autoimmune diseases, and cancer. However, an expert panel for the Institute of Medicine (IOM) has recently recommended that a level of 20 ng/mL (50 nM) was sufficient for 97.5% of the population, although up to 50 ng/mL (125 nM) was considered safe. For individuals between the ages of 1–70 yrs 600 iu vitamin was thought to be sufficient to meet these goals, although up to 4000 iu vitamin D was considered safe. These recommendations are based primarily on data from randomized placebo controlled clinical trials (RCT) that evaluated falls and fractures; data sup-porting the non skeletal effects of vitamin D were considered too preliminary to be used in their recommendations because of lack of RCT for these other actions. The lower end of these recom-mendations has been considered too low and the upper end too restrictive by a number of vitamin D experts, but the call for better clinical data especially for the non skeletal actions is well taken. These guidelines—at least with respect to the lower recommended levels of vitamin D supplementation—are unlikely to correct vitamin D deficiency in individuals with obesity, dark complex-ions, limited capacity for sunlight exposure, or malabsorption. Furthermore, a large body of data from animal and cell studies as well and epidemiologic associations support a large range of beneficial actions of vitamin D that with adequate RCT data may alter these IOM recommendations. Vitamin D deficiency or insufficiency can be treated by higher dosages (4000 units per day or 50,000 units per week for several weeks). No other vitamin D metabolite is indicated. Because the half-life of vitamin D3 metab-olites in blood is greater than that of vitamin D2, there may be some advantage to using vitamin D3 supplements, although when administered on a daily or weekly schedule these differences may be moot. The diet should also contain adequate amounts of cal-cium and phosphate.
The major sequelae of chronic kidney disease that impact bone mineral homeostasis are deficient 1,25(OH)2D production, reten-tion of phosphate with an associated reduction in ionized calcium levels, and the secondary hyperparathyroidism that results from the parathyroid gland response to lowered serum ionized calciumand low 1,25(OH)2D. FGF23 levels are also increased in this disorder in part due to the increased phosphate, and this can fur-ther reduce 1,25(OH)2D production by the kidney. With impaired 1,25(OH)2D production, less calcium is absorbed from the intes-tine and less bone is resorbed under the influence of PTH. As a result hypocalcemia usually develops, furthering the development of secondary hyperparathyroidism. The bones show a mixture of osteomalacia and osteitis fibrosa.
In contrast to the hypocalcemia that is more often associated with chronic kidney disease, some patients may become hypercal-cemic from overzealous treatment with calcium. However, the most common cause of hypercalcemia is the development of severe secondary (sometimes referred to as tertiary) hyperparathyroidism. In such cases, the PTH level in blood is very high. Serum alkaline phosphatase levels also tend to be high. Treatment often requires parathyroidectomy. A less common circumstance leading to hyper-calcemia is development of a form of bone disease characterized by a profound decrease in bone cell activity and loss of the calcium buffering action of bone (adynamic bone disease). In the absence of kidney function, any calcium absorbed from the intestine accu-mulates in the blood. Such patients are very sensitive to the hyper-calcemic action of 1,25(OH)2D. These individuals generally have a high serum calcium but nearly normal alkaline phosphatase and PTH levels. The bone in such patients may have a high aluminum content, especially in the mineralization front, which blocks nor-mal bone mineralization. These patients do not respond favorably to parathyroidectomy. Deferoxamine, an agent used to chelate iron , also binds aluminum and is being used to treat this disorder. However, with the reduction in use of aluminum-containing phosphate binders, most cases of adynamic bone dis-ease are not associated with aluminum deposition but are attributed to overzealous suppression of PTH secretion.
The choice of vitamin D preparation to be used in the setting of chronic kidney disease depends on the type and extent of bone disease and hyperparathyroidism. Individuals with vitamin D deficiency or insufficiency should first have their 25(OH)D levels restored to normal (above 30 ng/mL) with vitamin D. 1,25(OH)2D3 (calcitriol) rapidly corrects hypocalcemia and at least partially reverses secondary hyperparathyroidism and osteitis fibrosa. Many patients with muscle weakness and bone pain gain an improved sense of well-being.Two analogs of calcitriol—doxercalciferol and paricalcitol—are approved for the treatment of secondary hyperparathyroidism of chronic kidney disease. Their principal advantage is that they are less likely than calcitriol to induce hypercalcemia for any given reduc-tion in PTH. Their greatest impact is in patients in whom the use of calcitriol may lead to unacceptably high serum calcium levels.
Regardless of the drug used, careful attention to serum calcium and phosphate levels is required. A calcium × phosphate product (in mg/dL units) less than 55 is desired with both calcium and phos-phate in the normal range. Calcium adjustments in the diet and dialysis bath and phosphate restriction (dietary and with oral inges-tion of phosphate binders) should be used along with vitamin D metabolites. Monitoring of serum PTH and alkaline phosphatase levels is useful in determining whether therapy is correcting or preventing secondary hyperparathyroidism. In patients on dialysis, a PTH value of approximately twice the upper limits of normal is considered desirable to prevent adynamic bone disease. Although not generally available, percutaneous bone biopsies for quantita-tive histomorphometry may help in choosing appropriate therapy and following the effectiveness of such therapy, especially in cases suspected of adynamic bone disease. Unlike the rapid changes in serum values, changes in bone morphology require months to years. Monitoring of serum vitamin D metabolite levels is useful for determining adherence, absorption, and metabolism.
A number of gastrointestinal and hepatic diseases cause disordered calcium and phosphate homeostasis, which ultimately leads to bone disease. The bones in such patients show a combination of osteoporosis and osteomalacia. Osteitis fibrosa does not occur, in contrast to renal osteodystrophy. The important common feature in this group of diseases appears to be malabsorption of calcium and vitamin D. Liver disease may, in addition, reduce the produc-tion of 25(OH)D from vitamin D, although its importance in patients other than those with terminal liver failure remains in dispute. The malabsorption of vitamin D is probably not limited to exogenous vitamin D as the liver secretes into bile a substantial number of vitamin D metabolites and conjugates that are nor-mally reabsorbed in (presumably) the distal jejunum and ileum. Interference with this process could deplete the body of endoge-nous vitamin D metabolites in addition to limiting absorption of dietary vitamin D.
In mild forms of malabsorption, high doses of vitamin D (25,000–50,000 units three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease do not respond to vitamin D. Clinical experi-ence with the other metabolites is limited, but both calcitriol and calcifediol have been used successfully in doses similar to those recommended for treatment of renal osteodystrophy. Theoretically, calcifediol should be the drug of choice under these conditions, because no impairment of the renal metabolism of 25(OH)D to 1,25(OH)2D and 24,25(OH)2D exists in these patients. However, calcifediol is no longer available in the USA. Both calcitriol and 24,25(OH)2D may be of importance in reversing the bone dis-ease. Intramuscular injections of vitamin D would be an alterna-tive form of therapy, but there are currently no FDA-approved intramuscular preparations available in the USA.
As in the other diseases discussed, treatment of intestinal osteodystrophy with vitamin D and its metabolites should be accompanied by appropriate dietary calcium supplementation and monitoring of serum calcium and phosphate levels.
Osteoporosis is defined as abnormal loss of bone predisposing to fractures. It is most common in postmenopausal women but also occurs in men. The annual direct medical cost of fractures in older women and men in the USA is estimated to be 17–20 billion dollars per year, and is increasing as our population ages. Osteoporosis is most commonly associated with loss of gonadal function as in menopause but may also occur as an adverse effect of long-term administration of glucocorticoids or other drugs, including those that inhibit sex steroid production; as a manifesta-tion of endocrine disease such as thyrotoxicosis or hyperparathy-roidism; as a feature of malabsorption syndrome; as a consequence of alcohol abuse and cigarette smoking; or without obvious cause (idiopathic). The ability of some agents to reverse the bone loss of osteoporosis is shown in Figure 42–5. The postmenopausal form of osteoporosis may be accompanied by lower 1,25(OH)2D levels and reduced intestinal calcium transport. This form of osteopo-rosis is due to reduced estrogen production and can be treated with estrogen (combined with a progestin in women with a uterus to prevent endometrial carcinoma).
However, concern that estro-gen increases the risk of breast cancer and fails to reduce or may actually increase the development of heart disease has reduced enthusiasm for this form of therapy, at least in older individuals.
Bisphosphonates are potent inhibitors of bone resorption. They increase bone density and reduce the risk of fractures in the hip, spine, and other locations. Alendronate, risedronate, iban-dronate, and zoledronate are approved for the treatment ofosteoporosis, using daily dosing schedules of alendronate, 10 mg/d, risedronate, 5 mg/d, or ibandronate, 2.5 mg/d; or weekly schedules of alendronate, 70 mg/wk, or risedronate, 35 mg/wk; or monthly schedules of ibandronate, 150 mg/month; or quarterly (every 3 months) injections of ibandronate, 3 mg; or annual infusions of zoledronate, 5 mg. These drugs are effective in men as well as women and for various causes of osteoporosis.
As previously noted, estrogen-like SERMs (selective estrogen receptor modulators) have been developed that prevent the increased risk of breast and uterine cancer associated with estrogen while maintaining the benefit to bone. The SERM raloxifene is approved for treatment of osteoporosis. Like tamox-ifen, raloxifene reduces the risk of breast cancer. It protects against spine fractures but not hip fractures—unlike bisphosphonates, denosumab, and teriparatide, which protect against both. Raloxifene does not prevent hot flushes and imposes the same increased risk of venous thromboembolism as estrogen. To counter the reduced intestinal calcium transport associated with osteoporosis, vitamin D therapy is often used in combination with dietary calcium supple-mentation. There is no clear evidence that pharmacologic doses of vitamin D are of much additional benefit beyond cyclic estrogens and calcium supplementation. However, in several large studies, vitamin D supplementation (800 IU/d) with calcium has been shown to improve bone density, reduce falls, and prevent fractures. Calcitriol and its analog, 1α(OH)D3, have also been shown to increase bone mass and reduce fractures. Use of these agents for osteoporosis is not FDA-approved, although they are used for this purpose in other countries.
Teriparatide, the recombinant form of PTH 1-34, is approvedfor treatment of osteoporosis. Teriparatide is given in a dosage of 20 mcg subcutaneously daily. Teriparatide stimulates new bone formation, but unlike fluoride, this new bone appears structurally normal and is associated with a substantial reduction in the inci-dence of fractures. Teriparatide is approved for only 2 years of use. Trials examining the sequential use of teriparatide followed by a bisphosphonate after 1 or 2 years are in progress and look promis-ing. Use of teriparatide with a bisphosphonate has not shown greater efficacy than the bisphosphonate alone.
Calcitonin is approved for use in the treatment of postmeno-pausal osteoporosis. It has been shown to increase bone mass and reduce fractures, but only in the spine. It does not appear to be as effective as bisphosphonates or teriparatide.
Denosumab, the RANKL inhibitor, has recently beenapproved for treatment of postmenopausal osteoporosis. It is given subcutaneously every 6 months in 60 mg doses. Like the bisphosphonates it suppresses bone resorption and secondarily bone formation. Denosumab reduces the risk of both vertebralcand nonvertebral fractures with comparable effectiveness to the potent bisphosphonates.
Strontium ranelate has not been approved in the USA for thetreatment of osteoporosis but is being used in Europe, generally at a dose of 2 g/d.
These disorders usually manifest in childhood as rickets and hypo-phosphatemia, although they may first present in adults. In both X-linked and autosomal dominant hypophosphatemia, biologi-cally active FGF23 accumulates, leading to phosphate wasting in the urine and hypophosphatemia. In autosomal dominant hypo-phosphatemia, mutations in the FGF23 gene replace an arginine required for hydrolysis and result in increased FGF23 stability. X-linked hypophosphatemia is caused by mutations in the gene encoding the PHEX protein, an endopeptidase. Initially, it was thought that FGF23 was a direct substrate for PHEX, but this no longer appears to be the case. Tumor-induced osteomalacia is a similar acquired syndrome in adults that results from overexpres-sion of FGF23 in tumor cells. The current concept for all of these diseases is that FGF23 blocks the renal uptake of phosphate and blocks 1,25(OH)2D production leading to rickets in children and osteomalacia in adults. Phosphate is critical to normal bone min-eralization; when phosphate stores are deficient, a clinical and pathologic picture resembling vitamin D–dependent rickets develops. However, affected children fail to respond to the stan-dard doses of vitamin D used in the treatment of nutritional rickets. A defect in 1,25(OH)2D production by the kidney has also been noted, because the serum 1,25(OH)2D levels tend to be low in comparison with the degree of hypophosphatemia observed. This combination of low serum phosphate and low or low-normal serum 1,25(OH)2D provides the rationale for treating these patients with oral phosphate (1–3 g daily) and calcitriol (0.25–2 mcg daily). Reports of such combination therapy are encouraging in this otherwise debilitating disease, although pro-longed treatment often leads to secondary hyperparathyroidism.
These distinctly different autosomal recessive diseases present as childhood rickets that do not respond to conventional doses of vitamin D. Type I vitamin D–dependent rickets, now known as pseudovitamin D deficiency rickets, is due to an isolated deficiency of 1,25(OH)2D production caused by mutations in 25(OH)-D-1α-hydroxylase (CYP27B1). This condition can be treated with vitamin D (4000 units daily) or calcitriol (0.25–0.5 mcg daily). Type II vitamin D–dependent rickets, now known as hereditary vitamin D resistant rickets, is caused by mutations in the gene for the vitamin D receptor. The serum levels of 1,25(OH)2D are very high in type II but inappropriately low for the level of calcium in type I vitamin D–dependent rickets. Treatment with large doses of calcitriol has been claimed to be effective in restoring normocalce-mia in some patients, presumably those with a partially functional vitamin D receptor, although many patients are completely resistant to all forms of vitamin D. Calcium and phosphate infu-sions have been shown to correct the rickets in some children, similar to studies in mice in which the VDR gene has been deleted. These diseases are rare.
Patients with nephrotic syndrome can lose vitamin D metabolites in the urine, presumably by loss of the vitamin D-binding protein. Such patients may have very low 25(OH)D levels. Some of them develop bone disease. It is not yet clear what value vitamin D therapy has in such patients, because therapeutic trials with vita-min D (or any vitamin D metabolite) have not yet been carried out. Because the problem is not related to vitamin D metabolism, one would not anticipate any advantage in using the more expen-sive vitamin D metabolites in place of vitamin D.
Individuals with idiopathic hypercalciuria, characterized by hyper-calciuria and nephrolithiasis with normal serum calcium and PTH levels, have been divided into three groups: (1) hyperabsorbers, patients with increased intestinal absorption of calcium, resulting in high-normal serum calcium, low-normal PTH, and a secondary increase in urine calcium; (2) renal calcium leakers, patients with a primary decrease in renal reabsorption of filtered calcium, lead-ing to low-normal serum calcium and high-normal serum PTH; and (3) renal phosphate leakers, patients with a primary decrease in renal reabsorption of phosphate, leading to increased 1,25(OH)2D production, increased intestinal calcium absorption, increased ionized serum calcium, low-normal PTH levels, and a secondary increase in urine calcium. There is some disagreement about this classification, and many patients are not readily catego-rized. Many such patients present with mild hypophosphatemia, and oral phosphate has been used with some success in reducing stone formation. However, a clear role for phosphate in the treat-ment of this disorder has not been established.
Therapy with hydrochlorothiazide, up to 50 mg twice daily, or chlorthalidone, 50–100 mg daily, is recommended. Loop diuretics such as furosemide and ethacrynic acid should not be used because they increase urinary calcium excretion. The major toxicity of thiazide diuretics, besides hypokalemia, hypomagnesemia, and hyperglycemia, is hypercalcemia. This is seldom more than a biochemical observation unless the patient has a disease such as hyperparathyroidism in which bone turnover is accelerated. Accordingly, one should screen patients for such disorders before starting thiazide therapy and monitor serum and urine calcium when therapy has begun.
An alternative to thiazides is allopurinol. Some studies indicate that hyperuricosuria is associated with idiopathic hypercalcemia and that a small nidus of urate crystals could lead to the calcium oxalate stone formation characteristic of idiopathic hypercalcemia. Allopurinol, 100–300 mg daily, may reduce stone formation by reducing uric acid excretion.