1. Vitamin D and Calcium

Deficiency of vitamin D or calcium causes osteomalacia, rather than osteoporosis, but they often coexist (see Osteomalacia) and cannot be distinguished by DXA bone densitometry; it is crucial to ensure sufficient vitamin D and calcium intake. Recommended daily vitamin D intake of 600-800 IU/day is difficult to achieve by diet (unless high in fish) and sun exposure, particularly during winter months and for patients with intestinal malabsorption or during prolonged hospitalization or nursing home care. Oral vitamin D₃ (cholecalciferol) is given either as a universal supplement of 800-2000 IU/day or in doses titrated to achieve 25-hydroxyvitamin D (25-OHD) serum levels greater than or equal to 20 ng/mL (50 nmol/L) for most of the population. However, the 25-OHD serum levels should be maintained at 30 ng/mL (75 nmol/L) or higher for those "at risk": pregnant women, older adults, and those with osteoporosis or fragility fractures. Doses of vitamin D₃ above 4000 IU daily in adults are generally not advised (except in patients with intestinal malabsorption), since GI side effects or hypercalcemia may occur. Vitamin D should not be taken with topical calcipotriene (psoriasis) to avoid hypercalcemia. There are early observational data that imply an increased all-cause mortality at 25-OHD serum levels that are either excessively low or high, so the optimal therapeutic range for 25-OHD serum levels appears to be about 30-50 ng/mL (75-125 nmol/L).

A total elemental calcium intake at least 1000 mg/day is recommended for all adults and 1200 mg/day for postmenopausal women and men older than 70 years. Many individuals do not consume this amount of calcium, but a large prospective study of osteopenic postmenopausal women showed no improvement in BMD with high calcium consumption, and most cohort studies have shown no association between dietary calcium intake and fracture risk. Calcium supplementation (1 g/day or more) has not been shown to reduce the risk of hip or forearm fractures and reduces vertebral fractures by only 14% reduction. Therefore, normal and osteopenic individuals do not require calcium supplementation. Calcium supplements are reserved for patients with intestinal malabsorption or calcium-deficient diets (ie, low intake of dairy products, dark leafy greens, sardines, tofu, or fortified foods). Calcium citrate does not require acid for absorption and is preferred for patients receiving acid blockers. Calcium carbonate should be taken with food to enhance calcium absorption. Calcium supplements are usually taken along with vitamin D₃, and many commercial supplements contain the combination. Although calcium supplements are usually tolerated, some patients experience intestinal bloating and constipation. Taking calcium supplements with meals can reduce the risk of nephrolithiasis.

Some reports have indicated that calcium supplements increase the risk of MI. However, the Women's Health Initiative found that 7 years of vitamin D and calcium supplementation did not increase CVD but did increase the risk of nephrolithiasis by 13%.

2. Sex Hormones

Sex hormone replacement can prevent osteoporosis in hypogonadal women and men but is not an effective therapy for established osteoporosis. Low-dose transdermal systemic estrogen prevents osteoporosis in women with hypogonadism, including young patients with anorexia nervosa (see Hormone Replacement Therapy). Testosterone replacement or low-dose transdermal estradiol therapy prevents osteoporosis in men with severe testosterone deficiency (see Male Hypogonadism).

3. Bisphosphonates

Bisphosphonate therapy is indicated for patients with osteoporosis in the spine, total hip, or femoral neck or for patients with a pathologic spine fracture or a low-impact hip fracture. Bisphosphonates include intravenous zoledronic acid or pamidronate and oral alendronate, risedronate, or ibandronate. Ibandronate reduces vertebral fracture risk but not nonvertebral fracture risk. Bisphosphonates all work similarly, inhibiting osteoclast-induced bone resorption. They increase bone density significantly and all reduce the incidence of vertebral fractures; all but ibandronate have been demonstrated to also reduce the risk of nonvertebral fractures. Bisphosphonates have also been effective in preventing corticosteroid-induced osteoporosis. Another possible advantage is a reduction in adverse cardiovascular events. Oral alendronate was associated with a 33% reduction in cardiovascular events in a Danish cohort. To ensure intestinal absorption, oral bisphosphonates must be taken in the morning with at least 8 oz of plain water at least 40 minutes before consumption of anything else. The patient must remain upright after taking bisphosphonates to reduce the risk of esophagitis. No dosage adjustments are required for patients with creatinine clearances above 35 mL/min. Bisphosphonates are excreted in urine and serum phosphate levels should be monitored in patients with kidney disease; bisphosphonates are relatively contraindicated in patients with CrCl below 35 mL/min. Bone density falls in 18% of patients during their first year of treatment with bisphosphonates, but 80% of such patients gain bone density with continued bisphosphonate treatment. The half-life of bisphosphonates in bone is about 10 years. Therefore, after 3 years, a DXA bone densitometry may be obtained. If the patient's T-score has risen above -2.5 and the patient has a relatively low fracture risk, the patient may have a bisphosphonate "drug holiday" for 3-5 years. However, for patients with continued osteoporosis and a high fracture risk, the bisphosphonate may be continued another 2 years. The usual treatment course with bisphosphonates is 3-5 years due to the increasing risk of atypical femoral fractures after that time.

Alendronate is administered orally once weekly as either a 70-mg standard tablet (Fosamax) or a 70-mg effervescent pH-buffered tablet (Binosto) that is easier to swallow for some patients and may reduce esophageal injury. Risedronate (Actonel) may be given once monthly as a 150-mg tablet. Risedronate is favored for women of childbearing age, since it has a shorter half-life and less bone retention than other bisphosphonates. Both medications reduce the risk of vertebral and nonvertebral fractures, but alendronate appears to be superior to risedronate in preventing nonvertebral fractures. Ibandronate sodium (Boniva) is taken once monthly in a dose of 150 mg orally. It reduces the risk of vertebral fractures but not nonvertebral fractures; its effectiveness has not been directly compared with other bisphosphonates.

For patients who cannot take oral bisphosphonates, intravenous bisphosphonates are available. They should not be given to patients with a creatinine clearance below 35 mL/min. Patients should receive at least 15 minutes of intravenous hydration prior to infusions. Zoledronic acid (Reclast) is a third-generation bisphosphonate and a potent osteoclast inhibitor. The dose is 5 mg intravenously over at least 15-30 minutes every 12 months. In a study of postmenopausal women with osteoporosis, once yearly intravenous zoledronic acid reduced the 3-year incidence of hip fractures by 41% (from 2.5% to 1.4%) and clinical vertebral fractures by 77% (from 2.6% to 0.5%). Pamidronate (Aredia) is given in doses of 30-60 mg by slow intravenous infusion in normal saline solution every 3-6 months.

SIDE EFFECTS OF BISPHOSPHONATES—Oral bisphosphonates can cause nausea, chest pain, and hoarseness. Erosive esophagus can occur, particularly in patients with hiatal hernia and gastroesophageal reflux. Although no increased risk of esophageal cancer has been conclusively demonstrated, the FDA recommends that oral bisphosphonates not be used by patients with Barrett esophagus.

Intravenous bisphosphonate therapy can cause side effects that are collectively known as the acute-phase response. This occurs in 42% of patients after the first infusion of zoledronic acid, usually within the first few days following the infusion; these side effects include fever, chills, or flushing (20%); musculoskeletal pain (20%); nausea, vomiting, or diarrhea (8%); nonspecific symptoms, such as fatigue, dyspnea, edema, headache, or dizziness (22%); and ocular inflammation (0.6%). Symptoms are transient, lasting several days and usually resolving spontaneously. They typically recur with subsequent doses but diminish in intensity with time. Symptoms may be treated with acetaminophen or NSAIDs. Loratadine may reduce musculoskeletal pain. The acute-phase response is usually less severe with intravenous pamidronate than with zoledronic acid; thus, intravenous pamidronate can replace zoledronic acid for subsequent treatments. Patients who experience an especially severe acute-phase response can be given prophylactic corticosteroids and ondansetron prior to subsequent bisphosphonate infusions. Intravenous zoledronic acid has caused seizures that may be idiosyncratic or due to hypocalcemia.

Osteonecrosis of the jaw is a rare complication of bisphosphonate therapy. A painful, necrotic, nonhealing lesion of the mandible or maxilla occurs, particularly after tooth extraction. It occurs twice as frequently in the mandible compared to the maxilla. The risk is increased with older age, in women, and in patients concomitantly receiving chemotherapy or corticosteroid therapy. About 95% of jaw osteonecrosis cases have occurred with intravenous high-dose therapy with zoledronic acid or pamidronate for patients with osteolytic metastases. Only about 5% of cases have occurred in patients receiving oral bisphosphonates or once-yearly bisphosphonate infusions for osteoporosis. The incidence of osteonecrosis is estimated to be about 1:100,000 patients treated for osteoporosis with oral bisphosphonates versus1:100 in patients being treated for cancer with intravenous bisphosphonates. The risk for osteonecrosis of the jaw with dental surgery can be approximated preoperatively with a serum level of C-telopeptide, a fragment of collagen released during bone remodeling. Bisphosphonates reduce C-telopeptide levels. There appears to be minimal risk of osteonecrosis with serum C-telopeptide levels greater than or equal to 150 pg/mL, moderate risk with levels of 100-149 pg/mL, and higher risk with levels less than 100 pg/mL. Patients receiving bisphosphonates must receive regular dental care and try to avoid dental extraction. Ideally, elective dental surgery should be completed before starting bisphosphonates. If dental surgery is required, bisphosphonate therapy is ordinarily stopped 3 months before the surgery and resumed about 1 month afterward if the bone has healed.

Atypical low-impact "chalkstick" fractures of the femoral shaft are an uncommon complication of bisphosphonate therapy. Asian women, however, experience a relative risk of atypical femur fracture that is 4.8 times higher than White women. Atypical fractures are subtrochanteric or diaphyseal, occur with little trauma, and are usually transverse as opposed to the more typical comminuted or spiral femoral shaft fractures. In more than 52,000 postmenopausal women taking bisphosphonates for 5 years or longer, a subtrochanteric fracture occurred in 0.22% during the subsequent 2 years; 27% of such fractures were bilateral. About 70% of affected patients had prodromal thigh pain prior to the fracture. The risk for atypical femoral fractures is particularly increased among Asian women, patients taking high-dose corticosteroids, and those receiving bisphosphonate treatment for more than 5 years. Teriparatide (a PTH analog) may be helpful to promote healing of such fractures. Despite this potential complication, the benefits of bisphosphonates outweigh the risks, particularly in non-Asian women. In a large cohort analysis, for every 10,000 women taking bisphosphonates for 3 years, 149 hip fractures were prevented and 2 atypical femur fractures occurred in White women, while 91 hip fractures were prevented and 8 atypical femur fractures occurred in Asian women.

In patients taking bisphosphonates, hypercalcemia is seen in 20% and serum PTH levels increase above normal in 10%, mimicking primary hyperparathyroidism. Hypocalcemia occurs frequently, resulting in secondary hyperparathyroidism; such patients may be treated with oral calcium salt supplements (500-1000 mg/day) and with oral vitamin D₃ (starting at 1000 U/day).

4. Denosumab

Denosumab (Prolia) is a monoclonal antibody that inhibits the proliferation and maturation of preosteoclasts into mature osteoclast bone-resorbing cells. It does this by binding to the osteoclast receptor activator of nuclear factor-kappa B ligand (RANKL). It is indicated for treatment of osteoporosis, major fragility fractures, or osteopenia with a high FRAX score in both men and women. It is also used for patients with high fracture risk who are receiving sex hormone suppression therapy for breast cancer or prostate cancer. Treatment reduces vertebral fractures by 68% and hip fractures by 40%. Denosumab is administered in doses of 60 mg subcutaneously every 6 months. Unlike bisphosphonates, denosumab can be given to patients with severe kidney disease. It has been relatively well tolerated, with an 8% incidence of flu-like symptoms. It can decrease serum calcium and should not be administered to patients with hypocalcemia. Other side effects include hypercholesterolemia, eczema and dermatitis, and pancreatitis. Denosumab may slightly increase the risk of serious infections (particularly ear, nose, throat, and GI), so it is not recommended for patients receiving immunosuppressants or high-dose corticosteroid therapy. In premenopausal women, denosumab should be used with great caution and with birth control, since denosumab has caused fetal teratogenicity in animal studies. With prolonged use, denosumab predisposes to atypical femoral fractures and osteonecrosis of the jaw and is additive to bisphosphonates in that regard.

Compared to oral bisphosphonates, denosumab appears to be slightly superior at improving BMD of the spine, total femur, and femoral neck and at reducing fracture risk after 2 years of therapy. Compared to intravenous zoledronic acid, denosumab has been somewhat superior at increasing BMD at the total femur and femoral neck, but the two have similar efficacy at improving spine BMD.

The effects of denosumab on bone wane quickly after 6 months, and patients can experience a dramatic increased risk of multiple vertebral fractures within 1-2 years following discontinuation of denosumab. Therefore, denosumab must be given on-schedule without drug holidays. Denosumab should not be discontinued without substituting another antiresorptive agent (bisphosphonate, estradiol, or selective estrogen receptor modulator [SERM]) or other therapy.

5. PTH and Pthrp Analogs

Teriparatide (Forteo) and abaloparatide (Tymlos) are analogs of PTH and PTHrP, respectively. They are indicated only for patients with osteoporosis who are at very high fracture risk, particularly those who have sustained severe or multiple vertebral fractures. These analogs are anabolic agents that stimulate the production of new collagenous bone matrix, particularly in vertebral trabecular bone that must be mineralized. Patients receiving teriparatide or abaloparatide must have sufficient intake of vitamin D and calcium. When given in a sequence with an antiresorptive agent, the preferred sequence is to first give a course of PTH/PTHrP analog therapy followed by a bisphosphonate or denosumab.

The teriparatide dose is 20 mg or 40 mg daily, and the abaloparatide dose is 80 mg daily; both are given subcutaneously daily for up to 2 years. These drugs dramatically improve bone density in most bones except the distal radius. They may also be used to promote healing of atypical femoral chalkstick fractures associated with bisphosphonate therapy. The recommended dose should not be exceeded, since both drugs have caused osteosarcoma in rats when administered long-term in very high doses. Due to the potential risk for osteosarcoma, patients are excluded from receiving teriparatide or abaloparatide if they have an increased risk of osteosarcoma due to the following: Paget disease of bone, unexplained elevations in serum alkaline phosphatase, prior radiation therapy to bones, open epiphyses, or a past history of osteosarcoma or chondrosarcoma. Side effects may include injection site reactions, orthostatic hypotension, arthralgia, muscle cramps, depression, or pneumonia. Hypercalcemia can occur and manifest as nausea, constipation, asthenia, or muscle weakness. These drugs are approved for only a 2-year course of treatment.

Teriparatide and abaloparatide should not be used for patients with hypercalcemia. Similarly, they should be used with caution in patients if they are also taking corticosteroids and thiazide diuretics along with oral calcium supplementation because hypercalcemia may develop.

Following a 2-year course of teriparatide or abaloparatide, bisphosphonates should be given to retain the improved bone density. Alternatively, for very severe osteoporosis, these drugs may be administered along with denosumab; combined treatment for 2 years is more effective than any other single therapy, but adverse effects of fatigue, joint pain, and nausea are very common.

6. Selective Estrogen Receptor Modulators (Serms)

These agents can prevent osteoporosis but are not effective therapy for established osteoporosis. Raloxifene 60 mg/day orally may be taken by postmenopausal women in place of estrogen for prevention of osteoporosis. Bone density increases about 1% over 2 years in postmenopausal women versus 2% increases with estrogen replacement. It reduces the risk of vertebral fractures by about 40% but does not appear to reduce the risk of nonvertebral fractures. Raloxifene produces a reduction in LDL cholesterol, but not the rise in HDL cholesterol seen with estrogen. It has no direct effect on coronary plaque. Unlike estrogen, raloxifene does not reduce hot flushes; in fact, it often intensifies them. It does not relieve vaginal dryness. Unlike estrogen, however, raloxifene does not cause endometrial hyperplasia, uterine bleeding, or cancer, nor does it cause breast soreness. The risk of breast cancer is reduced 76% in women taking raloxifene for 3 years. Since it is a potential teratogen, it is relatively contraindicated in women capable of pregnancy. Raloxifene increases the risk for thromboembolism and should not be used by women with such a history. Leg cramps can also occur. Tamoxifen is commonly administered to women for up to 5 years after resection of breast cancer that is estrogen receptor-positive. Tamoxifen has opposite effects on bone density in premenopausal versus postmenopausal women. In premenopausal women, tamoxifen causes a loss of vertebral bone mineral density of -1.44% yearly, whereas in postmenopausal women, tamoxifen causes an increase in vertebral bone mineral density of +1.17% yearly. Bazedoxifene is available as a fixed-dose combination of conjugated estrogens with a SERM (bazedoxifene) (0.45 mg/20 mg [Duavee]). It is FDA approved for the prevention of osteoporosis in postmenopausal women with an intact uterus. However, unlike raloxifene, it has not been shown to reduce the risk of breast cancer. Women taking this combination medication long-term experience an increased risk of thromboembolic events.

7. Calcitonin

Nasal salmon calcitonin is used primarily for its analgesic effect for the pain of acute osteoporotic vertebral compression fractures. It is ineffective for chronic pain. Its analgesic effect may be seen within 2-4 weeks. If it appears to be effective for analgesia, it is continued for up to 3 months. The usual dose is one spray (200 IU) once daily in alternating nostrils. Rhinitis and epistaxis occur commonly; less common reactions include flu-like symptoms, allergy, arthralgias, back pain, headache, and hypocalcemia. An injectable form (100 IU subcutaneously or intramuscularly every 1-2 days) can be used for vertebral fracture pain when the nasal formulation is not tolerated due to local reactions. Because its anti-osteoporosis effect is modest, calcitonin is only used in patients who cannot tolerate other therapies. Calcitonin increases the overall risk of malignancy by about 1.1%, particularly hepatic cancer, and has been withdrawn from the market in Canada and Europe.

8. Romosozumab

Romosozumab (Evenity) is an injectable monoclonal antibody that inhibits sclerostin, increasing new bone formation and decreasing bone resorption. In one large cohort of women with osteoporosis and fragility fractures, romosozumab treatment for 12 months followed by alendronate for 12 months resulted in a 48% lower risk of vertebral fractures and a 38% lower risk of hip fracture compared to women receiving alendronate alone. The dose is 210 mg subcutaneously monthly for up to 12 months. It is reserved for patients with very severe osteoporosis, such as those with multiple vertebral fractures. It should only be given to patients with a low risk of coronary disease or stroke since it may slightly increase the risk of adverse cardiovascular events.

9. Orthopedic Surgery

Percutaneous vertebroplasty or kyphoplasty may be considered for patients with vertebral compression fractures who fail conservative pain management. However, no prospective randomized study has adequately compared the effectiveness of these orthopedic procedures compared to conservative therapy.