INTRODUCTION — Transplantation is an established therapy for end-stage kidney, heart, lung, and liver diseases, as well as for several hematologic disorders. Improved survival of transplant recipients has raised awareness of post-transplant complications, including osteoporosis. Post-transplant osteoporosis and fracture occur in a substantial proportion of patients.
The pathogenesis, clinical manifestations, and management of bone loss after solid organ (with the exception of kidney) or stem cell transplantation will be reviewed here. Management of bone loss after kidney transplantation is discussed elsewhere. (See "Kidney transplantation in adults: Bone disease after kidney transplantation" and "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation".)
EPIDEMIOLOGY AND RISK FACTORS
Incidence — Osteoporosis and fracture frequently occur after solid organ or hematopoietic transplantation . In the past, fracture incidence rates ranging from 10 to 65 percent were reported (eg, 10 to 36 percent after heart transplantation and 24 to 65 percent after liver transplantation) [2-5]. In some [6,7], but not all , subsequent studies, the reported rate of post-transplant fracture was lower, possibly due to increased recognition of the problem, which has resulted in changes in immunosuppressive regimens (eg, reduction in dose and duration of glucocorticoids), earlier treatment for osteoporosis, and improvement in pre- and post-transplantation nutrition.
Risk factors — Transplant-related osteoporosis and fracture are due to both pre- and post-transplant factors (table 1).
Pretransplant risk factors — Many patients undergoing transplantation already have low bone mineral density (BMD) . The mechanism appears to vary with the underlying disease:
●In patients with severe heart failure (New York Heart Association [NYHA] classes III and IV) who are candidates for cardiac transplantation, chronic kidney disease, vitamin D deficiency, secondary hyperparathyroidism, hypogonadism, chronic use of heparin and/or loop diuretics, and reduced physical activity may contribute to low BMD .
●In patients with primary biliary cholangitis, a toxin or toxins retained because of cholestasis may inhibit normal osteoblast function, causing a low-turnover form of osteoporosis (see "Evaluation and treatment of low bone mass in primary biliary cholangitis (primary biliary cirrhosis)"). In patients with cirrhosis due to other etiologies, excessive alcohol use, vitamin D deficiency, hypogonadism, and glucocorticoid use increase the risk of low BMD and osteoporosis .
●In patients with chronic lung disease, exposure to glucocorticoid therapy appears to be the primary risk factor for bone loss . Other risk factors include low body weight, smoking, physical inactivity, and vitamin D deficiency. In patients with cystic fibrosis, additional risk factors are hypogonadism, malnutrition, and malabsorption. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Musculoskeletal disorders'.)
Post-transplant risk factors — Patients lose bone rapidly after solid organ [13-16] and hematopoietic cell [17,18] transplantation (table 1). The bone loss is most rapid in the first three to six months after transplantation with subsequent slowing thereafter, the latter likely due to reductions in glucocorticoid and cyclosporine doses and resolution of pretransplant conditions, such as hyperbilirubinemia, that were deleterious to skeletal health. Rates of bone loss during the first year after heart [19,20] and liver  transplant are lower in recent years than they were in the 1990s and early 2000s. (See 'Incidence' above.)
A large proportion of post-transplant fractures occur during the brief phase of rapid bone loss that occurs in the first six months after transplantation (figure 1) [2,4,5,16,22]. The fracture rate is highest in patients with low pretransplant bone mass who lose bone rapidly; however, a substantial proportion of men with normal BMD before transplant may still fracture , and BMD changes do not always predict fracture risk . In a multivariate analysis of a nested case-control study of transplant recipients (kidney, liver, lung, and heart), a history of hyperthyroidism, pretransplant diabetes, fracture, or glucocorticoid use, as well as current exposure to antidepressants, narcotics, sirolimus, and loop diuretics were significant risk factors for post-transplant fracture . Use of bisphosphonates or calcitonin was also a predictor of fracture, likely indicating the presence of pretransplant osteoporosis.
The incidence of fracture falls as bone loss slows 6 to 24 months after transplantation. Studies of up to three to four years' duration show that lumbar spine (LS) BMD begins to recover during the second half of the first year after liver transplant, and during the second and third years after heart transplant and often returns to baseline, whereas femoral neck (FN) BMD remains below baseline levels [2,13,17,24,25]. As examples:
●In a prospective study of 280 patients undergoing allogeneic hematopoietic stem cell transplant, LS and FN BMD decreased by 5.8 and 8.5 percent, respectively, in the first year after transplant . Although LS BMD returned to baseline during the four-year study, FN BMD did not recover completely.
●In a retrospective study of 201 liver transplant recipients who underwent transplant between 2001 and 2011, T-scores declined significantly at the LS and FN six months after liver transplantation but increased thereafter at the LS, reaching pretransplantation values at two years and remaining stable thereafter . FN T-scores remained consistently lower than pretransplantation values. The prevalence of vertebral fractures increased from 56 percent at screening to 71 percent at one year after transplantation, with a fracture incidence of 34 percent. BMD changes did not predict fracture risk.
Effects of immunosuppressive regimens — Immunosuppressive drugs, particularly glucocorticoids, contribute to post-transplant bone loss and fracture. Glucocorticoids are administered in large doses initially and then tapered over time; dose increases for episodes of rejection or graft versus host disease are not uncommon. The doses of glucocorticoids used in modern-day transplantation, however, are much lower and tapered more rapidly than in the past .
The predominant effect of glucocorticoids on the skeleton is reduced bone formation. The decline in bone formation is mediated by direct inhibition of osteoblast proliferation and by increased apoptosis of osteoblasts and mature osteocytes. Glucocorticoids also increase bone resorption by increasing osteoclastogenesis. This effect is more prominent initially and diminishes over time, whereas inhibition of bone formation persists. In addition, glucocorticoids decrease secretion of androgens and estrogens, primarily mediated by inhibition of gonadotropin secretion, and increase secretion of parathyroid hormone (PTH). The etiology of glucocorticoid-induced osteoporosis is reviewed in detail separately. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)
Calcineurin inhibitors (cyclosporine and tacrolimus) may also contribute to post-transplant bone loss. There is some evidence that cyclosporine may increase bone turnover in humans. However, the effect of cyclosporine on bone metabolism in humans is less clear, with clinical evidence confounded by the presence of other illnesses or drugs that affect bone, particularly glucocorticoids (see "Drugs that affect bone metabolism", section on 'Cyclosporine'). Tacrolimus appears to have less adverse effect on bone than cyclosporine , and mycophenolate mofetil, rapamycin, and azathioprine have shown no effects on bone volume in a rat model .
PRETRANSPLANTATION EVALUATION — Prior to transplantation, we suggest the following initial evaluation in all patients:
●Bone mineral density (BMD, dual-energy x-ray absorptiometry [DXA]) of the hip or spine
●Spine radiographs, or vertebral fracture analysis (VFA) by DXA, to screen for vertebral fractures
●Serum 25-hydroxyvitamin D
Although bone loss slows or reverses after the first 6 to 12 months post-transplant, prevention of that early phase of bone loss is desirable, given the evidence for high fracture rates, particularly during the first post-transplant year. Low bone mass is common in adult patients awaiting transplant, and low BMD and fractures prior to transplant are risk factors for post-transplant fracture; therefore, measurement of BMD and screening for prevalent vertebral fractures prior to transplantation are widely recommended [3,16,18,27]. Screening is important even in asymptomatic patients, as the prevalence of vertebral fracture is high in adults aged ≥50 years, and approximately two-thirds of vertebral fractures are clinically silent .
Prevalent vertebral fractures may be detected before transplantation even in patients with relatively normal BMD and are likely to increase the risk of incident vertebral fractures after transplantation. Vitamin D deficiency is very common in recent transplant recipients [29,30] and patients awaiting organ transplantation.
●Osteoporosis – Patients who have a history of fracture, a prevalent vertebral fracture, or osteoporosis based on BMD (T-score ≤-2.5) before transplantation should be evaluated for secondary causes of bone loss (table 2 and table 3). (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women", section on 'Evaluation' and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men", section on 'Evaluation'.)
When a secondary cause (eg, vitamin D deficiency) is identified, appropriate treatment is recommended prior to transplant if possible. In addition to the treatment of secondary causes of osteoporosis, some patients may benefit from additional osteoporosis therapy, such as bisphosphonates, while awaiting transplant, particularly those with prevalent vertebral fractures or a history of other osteoporotic fractures (wrist, humerus, pelvis, hip, etc). (See 'Treatment of pretransplantation osteoporosis' below and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)
●Osteoporosis absent – Patients without osteoporosis based on BMD, without prevalent vertebral fractures, and without history of fragility fracture can defer medical therapy until after transplant, when kidney function is stabilized. (See 'Candidates for medical therapy' below.)
General recommendations for all patients — The same measures used to prevent or treat osteoporosis in the general population apply to transplant recipients. General recommendations that apply to all patients, regardless of the pretransplant bone mineral density (BMD) measurement, include the following:
●Counseling to stop smoking, mobilization soon after transplantation, and prevention of falls.
●Optimization of calcium and vitamin D intake. Prior to transplantation, most individuals should achieve the reference total daily calcium intake for their age group (from food sources and, if needed, supplements) (table 4) and vitamin D intake of 800 international units/day (20 micrograms/day). For individuals with chronic kidney disease, a lower calcium intake of 800 to 1000 mg daily is usually sufficient for neutral calcium balance. Higher vitamin D doses should be given if the patient has overt vitamin D deficiency (eg, 25-hydroxyvitamin D level <20 ng/mL [50 nmol/L]). Calcium and vitamin D, alone or in combination, do not prevent transplantation-related bone loss. However, it is established medical practice to ensure that patients are calcium and vitamin D replete when receiving pharmacologic therapy for osteoporosis, and the vast majority of randomized trials assessing antiresorptive therapies, such as bisphosphonates, have been carried out in the setting of concomitant calcium and vitamin D repletion. (See 'Choice of initial medical therapy' below.)
●Use of the lowest prednisone dose compatible with graft survival. However, bone loss has occurred in patients given prednisone in doses as low as 5 to 10 mg/day. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)
●Regular weightbearing exercise (30 minutes, three times per week) (see "Overview of the management of osteoporosis in postmenopausal women", section on 'Exercise'). Trials in cardiac transplant recipients suggest that resistance exercise training may be beneficial after transplantation [31,32]. In these trials, six months of resistance exercise training (including lumbar extension exercise and variable resistance exercises with a specialized fitness equipment) restored BMD toward pretransplantation values. However, these studies included a very small number of participants and may not be generalizable to all transplant recipients.
Treatment of pretransplantation osteoporosis — The treatment of patients who are diagnosed with osteoporosis prior to transplantation is similar to the treatment of osteoporosis in patients who are not transplant recipients.
●When a secondary cause (eg, vitamin D deficiency) is identified, it should be treated, if possible.
●For men and postmenopausal women with pretransplantation osteoporosis (T-score ≤-2.5, a prevalent vertebral fracture or prior fragility fracture, or a high risk of fracture by the Fracture Risk Assessment Tool [FRAX]), bisphosphonates are usually the first-line medical therapy. The treatment of osteoporosis in men and postmenopausal women is reviewed separately. (See "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)
●In contrast, medical therapy needs to be individualized in premenopausal women because of insufficient information on the potential for fetal harm in women who become pregnant while currently or recently receiving bisphosphonates (although this is rarely a problem in the immediate post-transplant period). The evaluation and treatment of premenopausal osteoporosis is reviewed separately. (See "Evaluation and treatment of premenopausal osteoporosis".)
Prevention of post-transplantation osteoporosis
Candidates for medical therapy — Although there is some lack of consensus about which patients should receive therapy to prevent bone loss and fractures, we suggest preventive medical therapy for all patients undergoing heart, liver, lung, or stem cell transplantation. We base our suggestion on studies showing that the most rapid bone loss occurs immediately after transplant; that fractures are common during the first post-transplant year, even in patients who do not have pretransplant osteoporosis by dual-energy x-ray absorptiometry (DXA); and that there is overlap in pretransplant BMD values between those who do and do not fracture [4,5]. In addition, most transplant patients receive glucocorticoid doses in excess of 7.5 mg prednisone daily (or equivalent) for three to six months after transplantation [16,27]. The duration of preventive therapy for transplant recipients may be as short as one year , which reduces concerns about adverse effects and cost of long-term bisphosphonate therapy. (See 'Choice of initial medical therapy' below and 'Duration of therapy' below.)
An alternative approach suggested by some specialists is to individualize preventive medical treatment, targeting patients with clinical risk factors for fracture (eg, age ≥65 years, previous fragility fracture, BMD T-score ≤-1.5). However, there is less evidence to support this approach, in part because patient recruitment in randomized trials of bisphosphonates for the prevention of transplantation-related osteoporosis was not based upon a particular BMD T-score criterion or clinical risk factor (other than transplantation) (see 'Efficacy' below). Thus, it is difficult to determine the best candidates for preventive therapy.
The optimal approach to the prevention of bone loss and fractures among kidney transplant recipients is reviewed separately. (See "Kidney transplantation in adults: Bone disease after kidney transplantation", section on 'Prevention of osteoporosis'.)
Choice of initial medical therapy — Bisphosphonates are considered the medical therapy of choice for the prevention of transplantation-related bone loss. Bisphosphonates should be used with caution in premenopausal women, however, because of insufficient information on the potential for fetal harm in women who become pregnant while receiving or shortly after discontinuing bisphosphonates. If bisphosphonates are contraindicated or not tolerated, calcitriol or estradiol/progesterone therapy (in women with hypogonadism) are alternatives. Treatment with calcitriol requires monitoring of serum and urinary calcium levels, making it less convenient than bisphosphonates in this setting. (See 'Calcitriol' below and 'Hormone replacement therapy' below and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Hypogonadal patients'.)
Bisphosphonates and calcitriol appear to prevent fractures. In a meta-analysis of 11 trials (780 patients) evaluating treatment with bisphosphonates (nine trials) or vitamin D analogs (two trials) versus placebo or no treatment after solid organ (liver, heart, kidney) transplantation, treatment conferred a significant reduction in the number of patients with fractures one year post-transplantation (26 versus 51, odds ratio [OR] 0.50, 95% CI 0.29-0.83) . Treatment also led to a reduction in the total number of fractures (38 versus 89, OR 0.37, 95% CI 0.22-0.60) and the number of vertebral fractures (29 versus 78, OR 0.24, 95% CI 0.07-0.78). Overall, the number of fracture events was small, limiting the precision of the meta-analysis. (See 'Efficacy' below and 'Calcitriol' below.)
Choice of bisphosphonate — Either oral or intravenous bisphosphonates can be administered. We favor intravenous zoledronic acid over oral bisphosphonates for patients at high risk of fracture, such as those with pretransplant osteoporosis, prior vertebral or other fragility fracture, pretransplant T-scores below -1.5, and those who find the weekly dosing schedule and requirement for post-alendronate fasting too burdensome, especially since post-transplant patients must take many oral medications.
There are few data to support the use of one bisphosphonate over another. Many of the trials used intravenous bisphosphonates due to ease of administration. In one of the only head-to-head trials comparing an intravenous bisphosphonate (zoledronic acid, single 5 mg infusion) with oral alendronate (70 mg weekly), both drugs were similarly effective in preventing bone loss at the hip with no difference in treatment effects in heart or liver transplant recipients . In contrast, lumbar spine (LS) BMD decreased in heart transplant patients who received alendronate and increased (+1.6 percent from baseline) in those who received zoledronic acid. In liver transplant recipients, both treatments led to increases in LS BMD.
Administration and dosing — We initiate preventive medical therapy as soon as kidney function is stabilized after heart, liver, lung, or stem cell transplantation (typically within one month after transplant). We continue it for the first 12 months and then reevaluate. (See 'Duration of therapy' below.)
The timing of bisphosphonate therapy may impact the efficacy of treatment. In a retrospective analysis of 60 patients who underwent lung transplantation, those who received treatment with zoledronic acid within six months of transplantation (either before or after) had gains in BMD at the LS and FN over three years of follow-up, whereas those who did not receive zoledronic acid within that timeframe exhibited declines in BMD at both sites . However, the control group comprised both patients who received zoledronic acid but outside the specified timeframe (n = 18) and those who did not receive therapy at all (n = 5); thus, the analysis could not clearly discriminate between the timing and provision of treatment.
The contraindications, dosing, prescribing instructions, and adverse effects of bisphosphonates are reviewed in detail elsewhere. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Practical management issues' and "Risks of bisphosphonate therapy in patients with osteoporosis" and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Contraindications to bisphosphonates'.)
Efficacy — Bisphosphonates attenuate glucocorticoid-induced bone loss, and they are frequently used for the prevention and treatment of osteoporosis in patients taking glucocorticoids (see "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Bisphosphonates'). Because post-transplant bone loss is highly associated with glucocorticoid treatment, bisphosphonates are also frequently used for the prevention of post-transplantation bone loss.
A number of trials and a meta-analysis have demonstrated that bisphosphonates are very effective for prevention of bone loss after solid organ or stem cell transplant [19,21,35-44].
●In a study of 99 patients undergoing stem cell transplantation, patients were randomly assigned to receive calcium (1000 mg/day) and vitamin D (800 international units/day) or the same calcium-vitamin D regimen plus pamidronate (60 mg intravenously six times over the first post-transplant year). Treatment with pamidronate prevented LS bone loss (0 percent in the pamidronate group versus -2.9 percent in the calcium group), and attenuated hip bone loss (-5.5 and -7.8 percent in the pamidronate and calcium-vitamin D groups, respectively) .
●In a trial of 62 adults undergoing liver transplantation who were randomly assigned to receive infusions of zoledronic acid (4 mg) or placebo within seven days of transplantation and 3, 6, 9, and 12 months later, the zoledronic acid group lost significantly less bone at the hip at all time points . In the spine, the zoledronic acid group lost less bone at three months, but the difference between the two groups was no longer significant at 12 months, because of improvements between 3 and 12 months in the placebo group. Zoledronic acid sometimes caused postinfusion hypocalcemia and temporary secondary hyperparathyroidism .
●In a trial of 98 patients receiving a liver transplant, subjects randomly assigned to alendronate (70 mg weekly) versus no alendronate had significant increases in LS (5.1 and 8.9 percent) and femoral neck (FN; 4.3 and 8.7 percent) BMD at 12 and 24 months, respectively, compared with the control group . All subjects received calcium (1000 mg daily) and calcitriol (0.5 mcg daily).
In addition to preventing bone loss, bisphosphonates appear to prevent fracture . A meta-analysis of nine trials evaluating treatment with bisphosphonates versus control (placebo or no treatment) on fracture outcomes after solid organ (liver, heart, kidney) transplantation showed a reduction in the proportion of patients with fracture at any site after treatment with bisphosphonates (OR 0.53, 95% CI 0.30-0.91) . The reduction in vertebral fractures did not reach statistical significance (OR 0.34, 95% CI 0.09-1.24). Only two of the trials in the meta-analysis were designed to explore fracture as a primary outcome [43,44].
In the majority of trials, individuals with serum creatinine concentrations above the upper limits of normal were excluded from participation. In general, there are limited data on the degree of kidney impairment at which bisphosphonate use should be avoided. Bisphosphonates are generally not recommended for those with creatinine clearance below 30 to 35 mL/min. This topic is reviewed elsewhere. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Use in chronic kidney disease' and "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation".)
Contraindications/intolerance to bisphosphonates — If bisphosphonates are contraindicated or not tolerated, calcitriol or estradiol/progesterone therapy (in women with hypogonadism) are alternatives. Men with symptomatic hypogonadism should receive testosterone replacement therapy. (See "Treatment of osteoporosis in men", section on 'Hypogonadism' and 'Hormone replacement therapy' below and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Contraindications to bisphosphonates'.)
●Efficacy – Calcitriol is also effective in preventing post-transplantation bone loss [19,46,47]. As an example, in one trial, 149 heart transplant recipients were randomly assigned to alendronate (10 mg orally daily) or calcitriol (0.25 micrograms orally twice daily) . Treatment was initiated within one month after transplantation; all patients also received calcium (945 mg daily) and vitamin D (1000 international units daily). Study participants were compared with a prospectively recruited reference group of 27 patients who declined to participate in the randomized trial.
At one year, the decrease in BMD was less marked for the alendronate and calcitriol groups than for the reference group at both the LS (-0.7 and -1.6 versus -3.2 percent) and the FN (-1.7 and -2.1 versus -6.2 percent). There was a trend toward fewer vertebral fractures with alendronate and calcitriol (6.8 and 3.6 versus 13.6 percent in the reference group). Hypercalciuria developed in significantly more patients treated with calcitriol than with alendronate (27 versus 7 percent).
In the meta-analysis described above that evaluated treatment with bisphosphonates (nine trials) or vitamin D analogs (two trials) versus placebo or no treatment after solid organ (liver, heart, kidney) transplantation, both treatments led to a significant reduction in the number of patients with fractures one year post-transplantation . (See 'Choice of initial medical therapy' above.)
●Dosing and monitoring – A typical initial dose of calcitriol is 0.25 micrograms twice daily. Serum calcium levels should be monitored as part of the usual post-transplantation biochemistry panel. If hypercalcemia develops, calcium supplements should be discontinued. If hypercalcemia persists, the calcitriol dose can be reduced to 0.25 mcg once daily, and if hypercalcemia is still present, calcitriol should be discontinued. Patients with persistent hypercalcemia after calcium supplements and calcitriol are discontinued require further evaluation to determine the etiology. (See "Diagnostic approach to hypercalcemia".)
Hormone replacement therapy — Estradiol/progesterone replacement is an alternative option for prevention of post-transplantation bone loss in hypogonadal premenopausal women. Men with symptomatic hypogonadism should receive testosterone replacement therapy (if not contraindicated). Adults with hypogonadism who are at high risk for fracture may require additional pharmacologic therapy. The diagnosis of hypogonadism and details of therapy are discussed elsewhere. (See "Clinical features and diagnosis of male hypogonadism" and "Testosterone treatment of male hypogonadism", section on 'Appropriate candidates' and "Evaluation and management of secondary amenorrhea".)
Estrogen-progestin therapy is not considered a first-line approach for the treatment of osteoporosis in postmenopausal women. (See "Menopausal hormone therapy: Benefits and risks" and "Menopausal hormone therapy in the prevention and treatment of osteoporosis".)
Many adults undergoing solid organ transplantation have temporary hypogonadism, most often related to the effects of glucocorticoids and chronic illness [48,49]. In some cases (eg, following chemotherapy and/or radiation therapy for hematopoietic stem cell transplantation), hypogonadism is permanent . In adults undergoing transplantation, hormone replacement therapy has been shown to slow bone loss [37,51-53]. (See "Treatment of osteoporosis in men", section on 'Patient selection' and "Treatment of osteoporosis in men", section on 'Hypogonadism' and "Evaluation and treatment of premenopausal osteoporosis", section on 'Secondary cause identified'.)
Other — Denosumab, a potent inhibitor of bone resorption approved for treatment of postmenopausal osteoporosis, has been evaluated in kidney transplant recipients, and more recently in a medically heterogeneous group of 63 long-term transplant recipients that included 14 who had received liver transplants . However, no studies of denosumab for prevention of bone loss during the first year after heart, liver, lung, or marrow transplantation have been reported. (See "Kidney transplantation in adults: Bone disease after kidney transplantation", section on 'Denosumab'.)
The concern about using denosumab to prevent transplantation osteoporosis is that treatment is often temporary during the period of higher-dose glucocorticoid treatment, and in postmenopausal women, discontinuation of denosumab leads to increased risk of bone loss and vertebral fractures, particularly multiple vertebral fractures. If denosumab is discontinued, administering an alternative therapy (typically a bisphosphonate) is advised to prevent rapid bone loss and vertebral fracture. Denosumab also leads to a small increase in risk of bacterial infections, another potential concern for its use in patients on immunosuppressive therapy. This issue is discussed in detail elsewhere. (See "Denosumab for osteoporosis", section on 'Increased fracture risk after stopping'.)
Although recombinant human parathyroid hormone (rPTH, teriparatide) has been shown to improve BMD in patients with glucocorticoid-induced osteoporosis, there are few studies evaluating parathyroid hormone (PTH) for the prevention of post-transplant osteoporosis (particularly non-kidney transplantation). (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Parathyroid hormone' and "Kidney transplantation in adults: Bone disease after kidney transplantation", section on 'Teriparatide'.)
Duration of therapy — We typically continue therapy for 12 months and then reevaluate. If BMD is stable during the first year after transplantation and glucocorticoids have been withdrawn completely or reduced to doses equivalent to <5 mg daily of prednisone, we typically stop bisphosphonate therapy.
There are few data to guide duration of therapy in transplant recipients. Given that LS BMD begins to recover in many patients within 12 months of transplantation, long-term treatment may be unnecessary. In some patients, 12 months of therapy may be adequate . Treatment duration should be based upon patient factors, such as ability to withdraw glucocorticoids, presence of other risk factors for low bone mass and fracture, and BMD measurements. (See "Osteoporotic fracture risk assessment", section on 'Clinical risk factor assessment'.)
Monitoring — Monitoring the response to therapy is important for identifying patients who may be able to discontinue therapy and for patients who are not responding to therapy. While there are a number of approaches to monitoring therapy, there is no consensus on the optimal approach. In the majority of patients, we suggest BMD measurements prior to and one year after transplantation, at a minimum.
In patients who require continued glucocorticoid therapy (eg, prednisone at ≥5 mg daily), or in those with T-scores below -2.5, continuation of bisphosphonates should be considered, with BMD measurements every one to two years. In patients who have successfully tapered off glucocorticoid therapy, we suggest annual BMD measurements for two years after transplantation with less frequent monitoring (every two to three years) thereafter.
Treatment of post-transplantation osteoporosis — Although bisphosphonates, calcitriol, and, in selected patients, hormone replacement therapy are efficacious in preventing bone loss at the time of transplantation, many patients are not evaluated for osteoporosis nor do they receive preventive therapy. Low bone mass and osteoporosis are commonly found in patients with a history of transplantation months or years in the past.
For those who remain on glucocorticoids, their treatment is similar to the treatment of osteoporosis in patients on glucocorticoids. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Bisphosphonates are efficacious in patients with persistent osteoporosis years after transplantation [55-57]. (See "Bisphosphonate therapy for the treatment of osteoporosis".)
rPTH has not been studied in populations receiving transplants other than kidney. Patients who have received total body irradiation during hematopoietic stem cell transplantation, who have primary or secondary elevations in PTH, or who have other hypercalcemic disorders are not candidates for rPTH therapy. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis".)
In one small study that included a few liver transplant recipients, denosumab was associated with a significant increase in BMD . Denosumab should not be given to patients with preexisting hypocalcemia until it is corrected. PTH and denosumab for the treatment of osteoporosis are reviewed separately. (See "Denosumab for osteoporosis".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology and risk factors – Osteoporosis and fracture frequently occur after solid organ or hematopoietic transplantation, though rates may be lower than in the past. The etiology is multifactorial (table 1). (See 'Epidemiology and risk factors' above.)
●Pretransplant evaluation – In patients undergoing organ or hematopoietic transplantation, we suggest measurement of pretransplant bone mineral density (BMD), assessment for prevalent vertebral fractures by spine radiographs or vertebral fracture assessment (VFA) by dual-energy x-ray absorptiometry (DXA), and measurement of serum 25-hydroxyvitamin D. (See 'Pretransplantation evaluation' above.)
●General recommendations for skeletal health – General measures to improve skeletal health in all transplant recipients include reducing the dose of glucocorticoids as soon as possible, smoking cessation, exercise, supplementation with calcium and vitamin D, and regular weightbearing exercise. (See 'General recommendations for all patients' above.)
●Treatment of pretransplantation osteoporosis – Patients with low pretransplant BMD (T-score ≤-2.5), a prevalent vertebral fracture, or a prior fragility fracture should be evaluated for secondary causes of bone loss (table 2 and table 3). (See 'Pretransplantation evaluation' above and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women", section on 'Evaluation' and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men", section on 'Evaluation' and "Evaluation and treatment of premenopausal osteoporosis", section on 'Evaluation'.)
The treatment of patients who are diagnosed with osteoporosis prior to transplantation is similar to the treatment of osteoporosis in patients who are not transplant recipients. For most adults with pretransplantation osteoporosis, bisphosphonates are usually first-line therapy. (See 'Treatment of pretransplantation osteoporosis' above and "Overview of the management of osteoporosis in postmenopausal women" and "Bisphosphonate therapy for the treatment of osteoporosis" and "Treatment of osteoporosis in men" and "Evaluation and treatment of premenopausal osteoporosis", section on 'Pharmacologic therapy for selected women'.)
●Prevention of post-transplantation osteoporosis
•Candidates for medical therapy – We suggest osteoporosis preventive therapy for all patients undergoing heart, liver, lung, or stem cell transplantation (Grade 2B). An alternative approach suggested by some specialists is to treat patients with clinical risk factors for fracture (age ≥65 years, previous fragility fracture) or BMD T-score ≤-1.5. (See 'Candidates for medical therapy' above.)
•Choice of initial medical therapy – For the prevention of post-transplant osteoporosis in most adults, we suggest bisphosphonates, rather than calcitriol (Grade 2B). Either oral or intravenous bisphosphonates can be administered as both have been shown to be effective in this setting. We favor intravenous zoledronic acid for patients at high risk for fracture (eg, osteoporosis at baseline, prevalent or prior vertebral or other fragility fracture, T-scores below -1.5 prior to beginning glucocorticoids) and for those who find the weekly dosing schedule of alendronate too burdensome. Prevention therapy should be initiated after transplant when kidney function is stabilized. (See 'Choice of initial medical therapy' above.)
Bisphosphonates should be used with caution in premenopausal women because of insufficient information on the potential for fetal harm in women who become pregnant while currently or recently receiving bisphosphonates. Calcitriol or hormone replacement therapy (in hypogonadal women) are alternative prevention options. (See 'Contraindications/intolerance to bisphosphonates' above and "Evaluation and treatment of premenopausal osteoporosis".)
•Monitoring – There is no consensus on the optimal strategy for monitoring patients on therapy. However, we typically measure BMD one year after transplantation and periodically thereafter, depending upon individual patient characteristics. (See 'Monitoring' above.)
●Treatment of post-transplantation osteoporosis – Despite the well-established risk of bone loss after transplantation and the availability of preventive therapies, many patients are not evaluated for osteoporosis, nor do they receive preventive therapy. Low bone mass and osteoporosis are commonly found in patients with a history of transplantation months or years in the past, and preferred treatment strategies depend on the specific clinical context. (See 'Treatment of post-transplantation osteoporosis' above.)
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