Regulation of serum calcium level is complex and dependent on the actions of vitamin D and parathyroid hormone (PTH). The primary effect of vitamin D is to enhance the absorption of calcium within the intestinal tract, whereas the effects of PTH are primarily mediated through regulation of calcium retention and excretion in the kidney (Figure 15). Measured calcium levels depend on the amount bound to albumin, which can be affected by nutrition and acid-base status. Hypoalbuminemia of any cause, such as cirrhosis or malignancy-related cachexia, will cause low total calcium levels. When albumin concentration is low, measurement of ionized calcium or calculation of corrected total calcium is required to accurately assess calcium levels.
The level of vitamin D is determined by both production in the skin in response to sunlight and by ingestion, either from food or supplements. While vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are available as supplements, the latter may be more efficacious due to greater potency, longer half-life, and being identical to that formed from ultraviolet light exposure. Activation of vitamins D2 and D3 requires hydroxylation initially by the liver and subsequently by the kidney, resulting in the active form of vitamin D, 1,25-dihydroxyvitamin D, calcitriol. 25-Hydroxyvitamin D is the storage form of vitamin D in the body, and measurement of 25-hydroxyvitamin D is the most appropriate test for assessing vitamin stores.
The initial response to a decline in serum calcium is an increase in PTH secretion, which decreases renal calcium excretion and increases calcium resorption from the bones to raise the serum calcium level. PTH also induces increased renal conversion of 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D, which improves the efficiency of intestinal calcium absorption. Continued PTH-mediated mobilization of calcium from bone over months to years in response to chronic negative calcium balance can lead to metabolic bone disease. In contrast, the skeleton, gut, and vitamin D metabolism do not significantly contribute to the correction of hypercalcemia. Instead, an increased filtered load and suppression of PTH secretion leads to robust excretion of calcium by the kidneys provided that effective circulating volume is adequate.
In addition to its role in mineral metabolism, the adult skeleton provides a reservoir of calcium, structural support for mobility, muscle attachment, and protection of vital organs. Bone remodeling allows for continuous skeletal adaptation and repair. Osteocytes coordinate bone remodeling, which is initiated by osteoclastic resorption then followed by much slower osteoblastic bone formation and mineralization of a collagen/protein matrix. The entire skeleton is remodeled approximately every 10 years.
Hypercalcemia is diagnosed when the calcium level exceeds normal levels, typically 10.5 mg/dL (2.6 mmol/L). Incidental finding of asymptomatic hypercalcemia on routine or screening blood tests is common.
Classic symptoms of hypercalcemia include polyuria, polydipsia, and nocturia. Additional symptoms may include anorexia, nausea, abdominal pain, constipation, and mental status changes. At higher levels, patients may become obtunded. Symptoms do not correlate linearly with serum calcium or PTH levels.
Severe hypercalcemia and hypercalciuria can lead to volume depletion and acute kidney injury, nephrolithiasis, or nephrocalcinosis. Skeletal manifestations reflect the underlying cause of hypercalcemia. Primary hyperparathyroidism may present as osteoporosis with fragility fractures and low bone density. Severe hyperparathyroidism from parathyroid carcinoma or secondary hyperparathyroidism due to kidney disease may be associated with bone pain and osteitis fibrosa cystica (a radiographic diagnosis). Hypercalcemia associated with lytic bone lesions is often the result of multiple myeloma or breast cancer.
Clues to the underlying cause of hypercalcemia include the severity, acuity of illness, and patient factors including concurrent illnesses. Hypercalcemia is categorized as mild (<12 mg/dL [3 mmol/L]), moderate (12-14 mg/dL [3–3.5 mmol/L]), or (severe >14 mg/dL [3.5 mmol/L]). When hypercalcemia is incidentally noted, repeat measurement is indicated. If hypercalcemia is confirmed, simultaneous measurement of serum calcium and PTH is a critical first step in diagnosing the cause and categorizing PTH-mediated and non–PTH-mediated hypercalcemia. Ionized calcium measurement is not helpful when the serum albumin level is normal or when there are no acute acid-base disorders. A thorough history and physical examination, as well as careful review of all medications including supplements, should be done in all patients with hypercalcemia.
Thiazide diuretics may cause mild hypercalcemia, especially in the setting of previously unrecognized, mild primary hyperparathyroidism. Hypercalcemia associated with lithium therapy is due to altered PTH secretion and may occur years after initiation of therapy. If possible, stopping the medication and rechecking calcium levels is a reasonable first step in management. If the calcium returns to normal, this suggests the medication was responsible.
PTH secretion decreases abruptly in response to a rise in serum calcium concentration. Therefore, an elevated or inappropriately normal (usually in the upper half of the reference range) PTH level in a patient with hypercalcemia is diagnostic of PTH-mediated hypercalcemia (Figure 16). Patients with an elevated PTH level but normal levels of calcium and vitamin D (normocalcemic primary hyperparathyroidism) may be managed similarly to those with asymptomatic primary hyperparathyroidism.
Primary hyperparathyroidism is typically caused by a solitary parathyroid adenoma. Women are more often affected than men, with a peak incidence in the seventh decade of life. Hypercalcemia is usually mild (within 1 mg/dL [0.25 mmol/L] of the upper limits of normal) and may be intermittently normal. Hypercalciuria is present in up to 30% of patients. Since PTH enhances kidney phosphate excretion, low or low-normal serum phosphorus concentrations support the diagnosis. Assessment of bone mineral density (BMD) with dual-energy x-ray absorptiometry (DEXA) should include the nondominant forearm, which can be particularly affected in patients with hyperparathyroidism. Although parathyroid imaging with sestamibi or neck ultrasound may localize an adenoma, the presence of an adenoma does not influence the decision to proceed with surgery in the setting of primary hyperparathyroidism. Imaging may be beneficial to the surgeon for planning surgical intervention. In the absence of a history of calcium nephrolithiasis, kidney imaging may be indicated to exclude occult stones if this finding would change management.
Dietary calcium intake should be approximately 1000 mg/d to avoid further increases in urine calcium excretion and PTH secretion. Measurement of 25-hydroxyvitamin D and cautious correction of vitamin D deficiency is important. Repletion is recommended in patients whose levels are below 30 ng/dL (75 nmol/L) with careful attention to urine calcium excretion and serum calcium once vitamin D values are greater than 30 ng/dL (75 nmol/L).
Changes in specific endpoints during monitoring that lead to a recommendation for parathyroid surgery are outlined in Table 43. Surgery results in a 95% cure rate and less than 1% rate of complications with an experienced surgeon using minimally invasive techniques. Preoperative correction of vitamin D deficiency is important to avoid postoperative hypocalcemia, which is the result of relative hypoparathyroidism and reduced PTH-mediated production of 1,25-dihydroxyvitamin D culminating in a rapid flux of calcium into bone (hungry bone syndrome). Patients with mild primary hyperparathyroidism commonly require calcium supplementation for up to 1 week after parathyroidectomy until residual parathyroid tissue normalizes serum calcium concentrations. Reassessment of BMD 1 year after parathyroidectomy may show improvement in BMD, especially at the spine.
Approximately one in three patients with asymptomatic primary hyperparathyroidism who initially defer surgery will develop indications for surgery during 10 to 15 years of observation. In those not deemed eligible or who elect not to undergo surgery, evaluation should include annual measurement of serum calcium, creatinine, and glomerular filtration rate (GFR). If kidney stones are suspected, imaging and 24-hour urine collection for biochemical stone profile should be considered. BMD should be obtained every 2 years, and spine imaging should be considered if the patient has significant loss of height or back pain in the setting of a normal BMD.
Parathyroid carcinoma is very rare, but may present with symptoms of severe hypercalcemia, with serum levels greater than 14 mg/dL (3.5 mmol/L) and markedly high PTH concentrations. Imaging is not useful and fine-needle aspiration is not recommended due to concerns of tumor seeding. The primary treatment is surgical resection. Unfortunately, 50% of patients may have residual or recurrent disease. Severe hypercalcemia in parathyroid carcinoma that is not amenable to surgery can be treated chronically with cinacalcet. Medical management options are limited, and patients are most likely to die from complications of hypercalcemia.
In patients with end-stage kidney disease, multigland hyperplasia results from chronic stimulus of PTH (a sequela of longstanding secondary hyperparathyroidism) due to poorly controlled hypocalcemia and hyperphosphatemia. In some cases of secondary hyperparathyroidism, the serum calcium can normalize if the hyperplasia and associated PTH secretion is robust. Chronic stimulation of the parathyroid glands can lead to autonomous production of PTH by all four glands, resulting in hypercalcemia. Tertiary hyperparathyroidism is most commonly recognized after kidney transplantation. Although historically treated with subtotal multigland parathyroidectomy, the hypercalcemia can be resolved in most patients by treatment with paricalcitol or cinacalcet.
Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant condition and the most common type of familial hypercalcemia. Patients are asymptomatic. The parathyroid glands and kidney detect serum calcium concentrations through the calcium-sensing receptor (CaSR). In FHH, inactivating mutation of the CaSR gene causes the parathyroid gland to perceive serum calcium concentrations as low, resulting in increased PTH secretion and a higher serum calcium level. Simultaneously, the mutated CaSR in the kidney increases kidney reabsorption of calcium, leading to paradoxical hypocalciuria in the setting of hypercalcemia.
Although these patients appear to have primary hyperparathyroidism, FHH is a benign condition that is not treated with parathyroidectomy. Hypercalcemia will not resolve with surgery. Patients do not have sequelae of hypercalcemia, such as stones or osteoporosis. Signs suggestive of FHH include: mild hypercalcemia since childhood; low 24-hour urine calcium excretion, especially if calcium-creatinine clearance ratio is below 0.01; and/or family history of parathyroidectomy without resolution of hypercalcemia. If clinically ambiguous, the diagnosis can be confirmed by CaSR genetic testing.
Primary hyperparathyroidism in adolescents and young adults may be the first sign of multiple endocrine neoplasia syndrome (MEN). Primary hyperparathyroidism is associated with MEN1 and MEN2A syndromes. If the family history reveals primary hyperparathyroidism, pituitary tumor, Zollinger-Ellison syndrome, early death from pancreatic neoplasm, pheochromocytoma, or medullary thyroid cancer, MEN is more likely and screening should be considered. In contrast to sporadic primary hyperparathyroidism, MEN syndromes have recurrence of hyperparathyroidism due to ongoing hyperplasia in the remaining parathyroid tissue after parathyroidectomy. MEN1 is associated with mutation of the tumor suppressor MEN1 gene, and MEN2A is associated with mutation of the RET gene. This is best managed in conjunction with or by an endocrinologist.
The differential diagnosis of hypercalcemia with suppressed PTH is broad. In patients with severe hypercalcemia, the history, symptoms, and findings may suggest the underlying cause. Treatment should commence without delay while awaiting results of laboratory testing. In PTH-independent hypercalcemic states, hypercalciuria can be severe and may precede hypercalcemia. PTH is usually undetectable but may be very low (<20 pg/mL [20 ng/L]) if hypercalcemia is mild.
The most common cause of non–parathyroid hormone-mediated hypercalcemia is malignancy, and it is typically severe (>14 mg/dL [3.5 mmol/L]). It is often the result of tumor-produced PTH-related protein (PTHrP) leading to extensive resorption of bone. Renal cell carcinoma, breast cancer, and squamous cell cancers are associated with PTHrP-related hypercalcemia. Rarely, locally mediated osteolysis from extensive skeletal metastases, typically in multiple myeloma and breast cancer, may cause efflux of calcium from bone resulting in significant hypercalcemia. For more information, see MKSAP 18 Hematology and Oncology.
Vitamin D–dependent hypercalcemia is associated with normal to elevated serum phosphorus levels because vitamin D enhances intestinal absorption of phosphorus and suppressed PTH secretion reduces kidney phosphorus excretion.
Unregulated conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D may occur in granulomatous tissue associated with fungal infection, tuberculosis, sarcoidosis, and lymphoma, leading to increased intestinal absorption of calcium. These conditions are associated with an inappropriately normal or frankly elevated 1,25-dihydroxyvitamin D level and suppressed PTH. Decreased serum and urine calcium after intake of calcium and vitamin D is restricted or a rapid decrease in calcium after glucocorticoid therapy (which inhibits the hydroxylation of 25-hydroxyvitamin D) is consistent with these disorders.
Vitamin D intoxication from chronic high-dose ingestion of vitamin D (typically >50,000 units daily in patients without malabsorptive conditions) and increased storage in fat causes protracted hypercalciuria, nephrolithiasis, impaired kidney function, and elevated 25-hydroxyvitamin D levels.
Ingestion of large amounts of calcium typically from antacid use (for example, calcium carbonate), especially with coexistent chronic kidney disease, causes milk-alkali syndrome.
Glucocorticoid and mineralocorticoid replacement and volume repletion resolve the mild hypercalcemia sometimes associated with Addisonian crisis.
Severe thyrotoxicosis occasionally causes hypercalcemia or hypercalciuria by increasing bone resorption.
Acute prolonged immobilization, as seen in spinal cord injuries, can cause large efflux of calcium from the skeleton through uncoupled bone remodeling with decreased osteoblastic activity despite increased osteoclastic activity. Patients with primary hyperparathyroidism or skeletal metastases are predisposed to hypercalcemia due to immobilization as are young patients where increased bone remodeling is normal.
Management is dependent on the severity of the hypercalcemia. If mild (<12 mg/dL [3 mmol/L]), treatment of the underlying disorder (for example, parathyroidectomy in primary hyperparathyroidism) is sufficient. Hospitalization may be needed in patients with acute kidney injury, mental status changes, or calcium levels above 12 mg/dL (3 mmol/L). Initial treatment of severe hypercalcemia is aggressive hydration to replete volume loss and increase kidney excretion of calcium. Loop diuretics are not recommended unless kidney failure or heart failure is present, in which case volume expansion should precede the administration of loop diuretics to avoid hypotension and further kidney injury. For the acutely symptomatic patient, subcutaneous calcitonin can be used; however, the drug effect wanes after 48 hours. Long-term management of hypercalcemia may require intravenous bisphosphonate therapy to prevent mobilization of calcium from the skeleton, but requires adequate kidney function. Glucocorticoids and restriction of calcium and vitamin D intake are uniquely beneficial in vitamin D–dependent hypercalcemia. Hemodialysis is reserved for the treatment of severe hypercalcemia in oliguric patients.
Signs and symptoms of hypocalcemia reflect its severity and acuity. Hypocalcemic disorders in outpatients are typically detected on screening blood tests and are mild, with serum calcium 7.5 to 8.9 mg/dL (1.9-2.2 mmol/L). It may also be detected during evaluation for low-intensity traumatic fractures or low bone mass. Most patients will be asymptomatic or report symptoms of intermittent paresthesia of the hands and feet or perioral numbness. Hypocalcemia due to chronic hypoparathyroidism can also be associated with cataract formation, basal ganglia calcification, papilledema, and dental enamel hypoplasia.
Patients with severe hypocalcemia may present with neuromuscular symptoms and signs. Carpopedal spasm with characteristic hand posture (flexion at metacarpophalangeal joints and extension at interphalangeal joints) may be spontaneous or triggered by transient distal limb ischemia during blood pressure assessment (Trousseau sign). Facial nerve hyperirritability and muscle spasm can be demonstrated by percussion of the facial nerve just anterior to the ear (Chvostek sign). Importantly, laryngospasm, seizure, myocardial dysfunction, and QT-interval prolongation leading to sudden cardiac death due to severe hypocalcemia (<7.5 mg/dL [1.9 mmol/L]) can occur without prodromal paresthesia or muscle cramping.
Hypocalcemia should be confirmed with a second measurement, which requires assessment of and correction for serum albumin concentrations. Ionized calcium measurement is indicated in the setting of fluctuating acid/base status. Simultaneous measurement of serum calcium, phosphorus, creatinine, and PTH is the next step. PTH should be elevated in the setting of hypocalcemia (see Figure 16).
Hypoparathyroidism is most commonly caused by inadvertent injury during anterior neck surgery (thyroidectomy, parathyroidectomy) or surgery to treat parathyroid gland hyperplasia, both of which present within a few hours of surgery. Depending on the extent of injury/resection, surgical hypoparathyroidism may last days to weeks. Permanent hypoparathyroidism may be partial or complete; the latter is associated with undetectable serum PTH levels and a higher prevalence of hyperphosphatemia.
Inappropriately normal PTH levels with concurrent hypocalcemia represents the former. Other causes of hypocalcemia due to insufficient PTH secretion include infiltrative disorders (hemochromatosis or Wilson disease), radiation, autoimmunity, and congenital disorders (such as 22q11.2 deletion syndrome). Chronic hypocalcemia with inappropriately normal PTH occurring within a family may represent an activating mutation of the CaSR gene. Hypomagnesemia, seen in the settings of malnutrition, alcoholism, and with use of loop diuretics and chronic proton pump inhibitor therapy, causes functional, reversible parathyroid hypofunction and must be excluded before a low or inappropriately normal PTH level is attributed to hypoparathyroidism. PTH resistance (pseudohypoparathyroidism) is a rare genetic cause of hypocalcemia.
Malnutrition and/or malabsorption of either or both vitamin D and calcium may be suspected based on clinical history (bariatric surgery, celiac disease) and confirmed by low serum 25-hydroxyvitamin D level or low 24-hour urine calcium excretion (a proxy indicator of calcium intake and absorption). The most common cause of acquired hypocalcemia is chronic kidney failure due to impaired production of 1,25-dihydroxyvitamin D and hyperphosphatemia. Hypercalciuria is most often idiopathic, but can also be due to chronic loop diuretic use. Rhabdomyolysis and tumor lysis syndrome increase serum phosphorus and calcium phosphate binding in the vascular space, causing low ionized calcium.
Hungry bone syndrome (rapid flux of calcium into bone after parathyroidectomy for severe primary hyperparathyroidism) and widespread osteoblastic metastases (prostate cancer, breast cancer) can cause hypocalcemia, as can saponification of calcium (and magnesium) in necrotic fat in acute pancreatitis.
Potent antiresorptive drugs, such as intravenous bisphosphonates and denosumab, can cause severe and protracted hypocalcemia by impairing physiologic efflux of calcium from the skeleton in patients with vitamin D deficiency. Therefore, it is important to assess vitamin D levels and correct deficiency before beginning treatment with an antiresorptive drug.
Because severe neuromuscular complications of hypocalcemia can occur in the absence of prodromal muscle tetany, severe hypocalcemia (<7.5 mg/dL [1.9 mmol/L]) requires urgent treatment with intravenous calcium. Slow administration through central intravenous access with electrocardiographic monitoring is preferred. Alternatively, teriparatide 20 µg twice per day rapidly eliminates hypocalcemic symptoms in acute postsurgical hypoparathyroidism (off-label indication).
Vitamin D supplementation 1000 to 4000 IU/d and oral calcium carbonate or calcium citrate at doses of 1 to 3 g/d in divided doses may normalize or sufficiently treat mild or chronic hypocalcemia. Calcitriol is needed in the setting of hypoparathyroidism with undetectable PTH and kidney failure because 1,25-dihydroxyvitamin D activation requires both PTH and sufficient kidney function.
In chronic hypoparathyroidism, goals of therapy are to eliminate symptoms while avoiding complications of therapy. A reasonable goal for most patients is a serum calcium concentration at or just below the reference range without hypercalciuria. Monitoring of urine calcium excretion is mandatory because hypercalciuria often limits therapy. Correction of coexisting hypomagnesemia is also required. Thiazide diuretics are commonly used because they decrease urine calcium excretion.
Initial treatment of hyperphosphatemia is reduction of dietary phosphorus but occasionally requires the addition of oral phosphate binders if serum phosphorus exceeds the normal range. Recombinant human PTH is available for patients who do not meet treatment goals with calcium and calcitriol therapy alone.
Bone mass, mineral content, and macro- and microarchitecture determine bone strength. Bone mineral density (BMD) reflects bone mass and mineral content and, in older adults, predicts deterioration of microarchitecture. This relationship and epidemiologic data underpin the use of BMD determined by dual-energy x-ray absorptiometry (DEXA) to diagnose low bone mass and refine fracture risk assessment in older adults. Fragility fractures (those occurring with minimal trauma, equivalent or less than a fall from a standing height) after age 50 indicate low bone strength and define clinical osteoporosis regardless of BMD. Skull, feet, and hand fractures cannot, by definition, be fragility fractures.
Low bone mass in adults may represent poor bone formation, bone loss, or both. Factors that can affect peak bone mass formation include genetic conditions, lifestyle factors, and poor health, especially in the second decade of life. Net loss of bone mass can occur in adults when osteoclastic bone remodeling is faster than osteoblastic bone formation. The list of risk factors for low bone mass and osteoporosis is extensive and is included in Table 44 and Table 45. Some patients, however, have osteoporosis caused by secondary causes. Testing for secondary causes is summarized in Table 46.
Current guidelines recommend screening average risk postmenopausal women beginning at age 65. Guidelines vary in their recommendations for routine screening for osteoporosis in men. The American College of Rheumatology recommends BMD testing within 6 months of starting long-term glucocorticoid therapy in adults 40 years of age and older and in adults under 40 years of age with risk factors for osteoporosis or a history of fragility fractures.
Patients with risk factors for low bone mass or osteoporosis, fragility fractures of the femur, vertebra (Figure 17), pelvis, humerus or radius, height loss of 4 cm (1.6 in) or more, or kyphosis, should have BMD testing earlier than standard screening recommendations. BMD may also be indicated if the risk of fractures is elevated based on the results of risk assessment tools such as the Simple Calculated Osteoporosis Risk Estimate (SCORE), Osteoporosis Self-Assessment Tool (OST), the Osteoporosis Risk Assessment Instrument (ORAI), and Fracture Risk Assessment Tool (FRAX). Table 47 lists recommendations for BMD testing and vertebral imaging.
Screening of younger women may be indicated if one or more risk factors for osteoporosis are present. In premenopausal women without risk factors, assessment of BMD for fracture risk is not advised or validated. However, if testing is done in an otherwise healthy person, results that are below age- and gender-matched averages (Z-score <0) generally do not require further evaluation or serial monitoring.
In postmenopausal women and men over 50 years of age, the diagnosis of osteopenia is determined by BMD testing (T-score between −1 and −2.5) alone, whereas osteoporosis can be diagnosed clinically based on the presence of fragility fractures, hip fracture, vertebral compression fracture, or by DEXA. Without secondary causes of low BMD or a fragility fracture, osteoporosis is diagnosed when the femur neck, total hip, nondominant radius, or composite (two or more consecutive diagnostic vertebrae) lumbar spine T-score is −2.5 or less, as defined by the World Health Organization. If hip or spine cannot be accurately measured by BMD, DEXA of the distal third of the radius can be used.
Diagnosis of osteoporosis in premenopausal women and men under 50 years can be made with diagnosis of a fragility fracture or low bone mass on DEXA defined by a Z-score less than −2, which indicates “low bone mass for age.”
BMD assessment using quantitative calcaneal ultrasonography may be used to screen for osteoporosis, but abnormal results require confirmation by DEXA. Quantitative CT provides a DEXA equivalent T-score, is not hindered by degenerative changes in the lumbar spine, and is highly sensitive for detection of vertebral compression fractures, but its cost and radiation exposure are greater and is not recommended for osteoporosis screening.
Non-modifiable factors are the most common cause of low bone mass, but there are many other causes (see Table 44 and Table 45). Low bone mass may be the presentation for conditions such as idiopathic hypercalciuria or celiac disease. All patients should have a thorough history and physical examination and additional testing based on findings (see Table 46). Although BMD may not be required in all patients to make the diagnosis of osteoporosis, it may be helpful to determine if additional testing is needed and to guide treatment.
Osteomalacia is most commonly caused by severe and prolonged vitamin D deficiency, which results in inadequate concentrations of calcium and/or phosphate in the bone, which in turn prevents mineralization of newly formed bone matrix. Unlike osteoporosis, osteomalacia does not result in permanent loss of bone structure. A period of months to years of disordered mineralization is required before bone strength is compromised.
Symptoms of osteomalacia include diffuse bone pain, bone tenderness to palpation (tibial plateau and sternum), and proximal muscle weakness; however, early osteomalacia may present only with low bone mass on DEXA and can be indistinguishable from osteoporosis without further testing. Very low BMD (Z-score ≤−2), low or low-normal serum calcium and phosphorus levels, very low 25-hydroxyvitamin D (<10 ng/mL [25 nmol/L]) level, and secondary hyperparathyroidism distinguishes osteomalacia from osteoporosis. Elevated serum alkaline phosphatase level is particularly suggestive of osteomalacia, although mild elevation can be seen with recent osteoporotic fracture. Radiographs may display an unusual distribution of fractures in severe osteomalacia (Figure 18). When bone pain is not explained by conventional radiographic findings in the setting of suspected osteomalacia, imaging with radionuclide bone scan or MRI may reveal fractures.
The goal of treatment is to optimize conditions for bone mineralization using supplementation to normalize serum 25-hydroxyvitamin D (>30 ng/mL [75 nmol/L]), calcium, and phosphorus concentrations. The skeletal response to treatment is reflected by gradual normalization of alkaline phosphatase level and symptom relief. Resolution of osteomalacia may take as long as 12 months; subsequent BMD testing will show significant increases and/or normalization of BMD.
Low bone mass and fragility fractures in young and middle-aged adults may result from genetic disorders (see Table 45). Patients with mild (type 1) osteogenesis imperfecta may present with a history of childhood fractures that decrease in frequency as adults. Hypermobility raises suspicion for Ehlers-Danlos and related syndromes. Hypophosphatasia should be suspected in middle-aged patients with fractures and serum alkaline phosphatase levels well below the reference range.
Exercise involving weight-bearing, resistance, and balance is important for bone health and may reduce fracture risk at any age, but especially in patients over 65 years. Although the measurable treatment effect may be small, calcium and vitamin D were universally supplemented in osteoporosis pharmacotherapy trials; the National Academy of Medicine recommends calcium intake of 1000 to 1200 mg/d, ideally from dietary sources. A calcium supplement may be used for patients whose diets are insufficient, but should not be recommended independent of dietary assessment and intervention. As many osteoporosis clinical trials, including those testing pharmacotherapy, sought to achieve 25-hydroxyvitamin D levels of at least 30 ng/mL (75 nmol/L), a vitamin D supplement of 1000 to 2000 IU/d may be appropriate in the context of osteoporosis care.
The goal of treatment is reduce risk of fractures in patients with osteoporosis or those at increased risk of fracture (primary prevention). The U.S. National Osteoporosis Foundation recommends pharmacologic treatment for patients with osteoporosis-related hip or spine fractures, those with a BMD T-score of −2.5 or less, and those with a BMD T-score between −1 and −2.5 with a 10-year risk of 3% or greater for hip fracture or risk of 20% or greater for major osteoporosis-related fracture as estimated by the Fracture Risk Assessment Tool (FRAX). Some studies suggest that different thresholds for initiation of treatment should be considered in other at-risk populations. The American College of Rheumatology recommends treatment for glucocorticoid-induced osteoporosis based on age, gender, and fracture risk.
Pharmacotherapy may also be used to prevent loss of BMD in postmenopausal women at risk of osteoporosis and to prevent or treat glucocorticoid-induced osteoporosis. Although estrogen therapy may be considered for management of vasomotor symptoms in postmenopausal women, it is no longer considered first-line therapy for prevention of osteoporosis. The FDA has recently approved a combination pill, bazedoxifene and conjugated estrogen, for prevention of postmenopausal osteoporosis. FDA-approved drugs for treatment of osteoporosis and options for prevention are listed in Table 48.
Oral bisphosphonates, alendronate and risedronate, are antiresorptive agents and are generally first-line treatment for osteoporosis in postmenopausal women and men over 50 years of age. They have been shown to reduce the risk for spine, hip, and non-vertebral fractures. Another bisphosphonate, ibandronate, has only shown efficacy in reducing vertebral fractures. In glucocorticoid-induced osteoporosis with moderate to high fracture risk, oral bisphosphonates are recommended as first-line therapy in adult men and women regardless of age. Intravenous zoledronic acid once a year is an option if patients experience upper gastrointestinal symptoms or have difficulty taking the medication as directed. An acute-phase response reaction including pyrexia and myalgia may occur after first administration in as many as one in three patients, but does not occur typically with subsequent administrations. Zoledronic acid is also effective in preventing fractures in patients with osteopenia, an effect not seen with other bisphosphonates. All bisphosphonates are contraindicated in patients with reduced kidney function (glomerular filtration rate [GFR] <35 mL/min/1.73 m2) and should not be given until vitamin D deficiency and hypocalcemia are treated, if present.
Rare side effects of antiresorptive agents are osteonecrosis of the jaw and atypical femur fracture. Osteonecrosis of the jaw may occur at any point in therapy; whereas the risk for atypical femur fracture appears to increase with duration of therapy. For most patients, the benefits in reduction of osteoporosis fractures far outweigh the risk of these uncommon side effects. A drug holiday can be considered after 3 years (intravenous) to 5 years (oral) of bisphosphonate treatment although the balance between the risks and benefits of extended therapy is unclear. Furthermore, the best means of patient selection for extended therapy is uncertain as fracture risk assessment does not predict benefit. Fracture risk with long-term alendronate, for example, does not vary by history of prior fracture, FRAX score, or pretreatment levels of bone turnover markers. Similarly, there are no data to guide the duration of the drug holiday, but factors taken into consideration may include the bisphosphonate used and whether BMD is maintained on DEXA.
Denosumab is a monoclonal antibody that inhibits osteoclast activation. When administered subcutaneously twice yearly, denosumab suppresses bone resorption, increases bone density, and reduces the incidence of osteoporotic fractures in men and women. Optimal duration of denosumab is uncertain but fracture risk may be reassessed after 5 to 10 years of therapy. The effects of denosumab are not sustained when treatment is stopped, and alternative antiresorptive therapy such as a bisphosphonate should be considered if denosumab is discontinued. Denosumab may be preferred in patients with stage 4 chronic kidney disease and in those intolerant of or incompletely responding to bisphosphonate therapy. Adverse effects include hypocalcemia, especially in older patients with vitamin D deficiency, and an increased rate of cellulitis and bronchitis. Medication-related osteonecrosis of the jaw and atypical femur fracture have been reported with denosumab use as well.
Teriparatide, rhPTH (1-34), is approved for use in postmenopausal women and men or women with glucocorticoid-induced osteoporosis who are at high risk of osteoporotic fracture. It is also used to improve bone mass in men with primary or hypogonadism-related osteoporosis at high risk of fracture. Abaloparatide, rhPTHrP (1-34), is approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture. Both agents stimulate bone formation and require daily subcutaneous injection. Treatment should be limited to 2 years. Improvement in BMD is most evident at the spine. To prevent the loss of newly formed bone, sequential therapy with an antiresorptive agent must begin within 1 month of completing the course of anabolic treatment.
Routine serial DEXA measurements of BMD are not indicated for follow-up of low-risk patients who do not have osteoporosis. Subsequent BMD testing depends on baseline BMD. Repeating after 15 years may be reasonable if the hip T-score is normal (>−1), while retesting at 2 years may be considered if the hip T-score is −2 to −2.4.
The primary reason for repeating BMD testing in patients taking antiresorptive agents is to detect treatment failure. Declining BMD, indicated by a statistically significant percent drop in g/cm2 of bone (not declining T-scores in subsequent DEXA scans) or a fracture while on treatment, raises concern for an unrecognized secondary cause, nonadherence, or insufficient response that necessitates reevaluation. The American College of Physicians recommends against monitoring of bone mineral density during treatment because data from several studies showed that women treated with antiresorptive treatment benefited from reduced fractures even if BMD did not increase. Instead follow-up management should include review of indication for treatment, monitoring of adherence to treatment, and reinforcement of lifestyle measures to prevent fractures, minimize bone loss, and avoid frailty. Drug holiday from antiresorptive therapy usually involves measurement of BMD to establish a baseline and repeated measurement in 2 to 3 years. Although this approach would ostensibly inform subsequent treatment decisions, it has not been validated.
The most appropriate test to assess adequacy of vitamin D is measurement of serum 25-hydroxyvitamin D, which reflects dietary and skin-derived vitamin D. At least 20 ng/mL (50 nmol/L) is recommended to prevent metabolic bone disease in otherwise healthy populations and generally can be met with an intake of 600 to 800 IU/d.
Routine screening for vitamin D deficiency is not recommended in healthy populations; however, testing for deficiency is appropriate in groups at high risk or in patients presenting with low bone mass, fractures, hypocalcemia, or hyperparathyroidism. In patients with bone, parathyroid, or calcium disorders, to raise blood levels consistently above 30 ng/dL (75 nmol/L) may require 1000 to 2000 U/d. Patients with malabsorption, chronic lack of sun exposure, BMI greater than 40, advanced liver disease, and medications interfering with vitamin D metabolism, such as phenytoin and phenobarbital, may require 2000 to 4000 U/d for repletion and maintenance of vitamin D stores as guided by 25 hydroxyvitamin D levels obtained 3 months after initiation of treatment.
Loading doses using 50,000 U/d of either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) once weekly for 8 weeks is appropriate in severe deficiency especially in the setting of malabsorption. Candidates for loading doses include: undetectable 25-hydroxyvitamin D, hypocalcemia, and osteomalacia due to vitamin D deficiency. Maintenance therapy of 1000 to 4000 U/d is recommended to maintain sufficiency after a loading dose.
Widespread public interest and a proliferation of scientific publications regarding vitamin D stem from established autocrine and paracrine effects in most tissues as well as extensive observational data associating 25-hydroxyvitamin D levels with extraskeletal health outcomes. However, intervention trials have not convincingly demonstrated a benefit of vitamin D supplementation on most disease outcomes, suggesting that low 25-hydroxyvitamin D levels may be a marker rather than a cause of ill health.
Although Paget disease of bone may present with localized symptoms, it is most commonly diagnosed in asymptomatic older patients presenting with elevated alkaline phosphatase levels or incidental radiographic findings. Commonly affected bones include the skull, spine, sacrum, pelvis, femur, and tibia. The skeletal site and extent of involvement including rate of bone turnover determine clinical features. Involvement of weight-bearing bones of the lower extremity may result in bone pain, deformity, or fracture. Involvement of a bone approximating a joint can contribute to degenerative joint disease (Figure 19). Expansion of Pagetic bone of the upper spine or skull base may cause spinal cord or cranial nerve compression.
Diagnosis is based on radiographic findings of thickening of cortical bone, coarsened trabecular markings, and distortion and expansion of involved bone. Biopsy is rarely needed. Serum alkaline phosphatase, a marker of increased bone turnover, is generally elevated but may not be elevated in some patients with longstanding disease that has become metabolically inactive. Alkaline phosphatase may be elevated in other conditions, including vitamin D deficiency, other metabolic bone disease (such as osteomalacia), or recent fracture. Therefore, all patients with suspected Paget disease of bone require assessment of serum calcium, 25-hydroxyvitamin D, and a whole-body radionuclide bone scan. If the bone scan reveals other skeletal sites suspicious for Paget disease of bone, radiography of those sites is required for further evaluation.
Management of Paget disease is based on symptoms, location of involvement, and disease activity. Indications for treatment include: bone pain; risk for fracture and progressive deformity that could compromise bone, joint, or neurologic function; and elevated alkaline phosphatase concentrations. Bisphosphonates, particularly a one-time dose of 5 mg of intravenous zoledronic acid, often achieve the treatment goal of reducing pain and normalizing of alkaline phosphatase for up to 5 years. Oral bisphosphonates may also be used, but duration of treatment is variable.
Annual alkaline phosphatase levels should be monitored. Retreatment is indicated if previously normalized levels of alkaline phosphatase exceed normal levels. Imaging is required if there is a dramatic rise in alkaline phosphatase levels or acceleration in symptoms, which raises a concern for the rare sarcomatous transformation of Pagetic bone.