Version May 2024
INTRODUCTION — The National Health and Nutrition Examination Survey (NHANES) national survey in the United States found that 27 percent of patients with osteoporosis had grade 3 chronic kidney disease (CKD) and 3 percent had estimated glomerular filtration rate (eGFR) lower than 35 mL/min/1.73 m2 (table 1) [1]. The management of osteoporosis in these patients is more complex than in patients without CKD and depends upon whether the patient also has coexisting chronic kidney disease-mineral and bone disorder (CKD-MBD), a constellation of findings including abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D; abnormalities in bone physiology including turnover, mineralization, volume, linear growth, or strength; and/or vascular or other soft tissue calcification. Because bone disorders are related to vascular calcifications, any treatments that modify bone may also impact the vasculature.
This topic will review the management of osteoporosis in patients with CKD. The diagnosis and evaluation is reviewed separately. (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation".)
The pathogenesis, diagnosis, and management of other aspects of MBD in patients with CKD are also reviewed elsewhere.
●(See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
●(See "Evaluation of renal osteodystrophy".)
●(See "Management of secondary hyperparathyroidism in adult patients on dialysis".)
LIFESTYLE MEASURES — Lifestyle measures, including adequate calcium and vitamin D, exercise, cessation of smoking, avoiding excessive alcohol intake, and fall prevention, are important in all patients at high risk for fracture. These are reviewed briefly below as pertains to chronic kidney disease (CKD) and in more general detail elsewhere. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Lifestyle measures to reduce bone loss' and "Treatment of osteoporosis in men", section on 'Lifestyle measures'.)
Calcium and vitamin D — An optimal diet for the prevention of fracture includes an adequate intake of calories (to avoid malnutrition), calcium, and vitamin D.
●eGFR ≥30 mL/min/1.73 m2 – Patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 who have no biochemical evidence of CKD-MBD (mineral bone disorder; eg, no evidence of hyperparathyroidism, hyperphosphatemia) should have similar calcium and vitamin D intake as patients without CKD. Calcium and vitamin D supplementation are reviewed in detail elsewhere. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Summary and recommendations'.)
●eGFR <30 mL/min/1.73 m2 – For patients with eGFR <30 mL/min/1.73 m2, we suggest a total calcium intake (diet plus supplement) of 1200 mg/day, with 500 mg/day or less of this total amount provided by calcium supplementation. The difference between the calcium provided by supplementation and total calcium intake should be provided by nutritional means (table 2). Since dairy products also contain phosphorus, nondairy sources of calcium (calcium-fortified orange juice, soy products, vegetables) may be preferred in some patients. We also suggest 800 international units of vitamin D (cholecalciferol or ergocalciferol) daily.
The effect of calcium and vitamin D supplementation on fracture risk or falls in patients with CKD and eGFR <30 mL/min/1.73 m2 has not been adequately studied. Thus, recommendations regarding calcium and vitamin D supplementation for the management of osteoporosis in patients with eGFR <30 mL/min/1.73 m2 are mostly based upon low-quality evidence and data extrapolated from patients without severe CKD. The data from postmenopausal women showing the benefit of calcium and vitamin D supplementation in reducing the risk of falls and hip fractures suggest that there may be a benefit to repleting vitamin D in patients with more severe CKD, and the potential benefit of vitamin D (cholecalciferol or ergocalciferol) repletion appears to be far greater than the risks [2].
In contrast, excess calcium supplementation (as opposed to calcium obtained by nutritional means) in patients with eGFR <30 mL/min/1.73 m2 may be associated with an increase in arterial calcification and cardiovascular disease [3,4]. This negative relationship may be related to many cofactors seen in more severe CKD, including hyperphosphatemia, hyperparathyroidism, and elevated fibroblast growth factor 23 (FGF23). (See "Vascular calcification in chronic kidney disease", section on 'Oral calcium intake'.)
In patients with normal or mild impairment in glomerular filtration rate (GFR; eg, eGFR >60 mL/min/1.73 m2), hypercalcemia does not typically occur with vitamin D supplementation until serum 25-hydroxyvitamin D levels are >150 ng/mL. This is due to the great capacity of the kidney to increase urine calcium clearance. However, in patients with eGFR <60 mL/min/1.73 m2, this homeostatic adaptation is impaired, and lower serum 25-hydroxyvitamin D levels may induce hypercalcemia. Hence, monitoring the serum calcium more closely in these patients is important, particularly when eGFR is <30 mL/min/1.73 m2. (See 'Monitoring therapy' below.)
Fall prevention — Fall prevention strategies are particularly important in patients with eGFR <15 mL/min/1.73 m2, who are often frail and have a high frequency of falling. Patients with severe CKD often have sarcopenia, a systemic condition of muscle mass deficiency and poor muscle strength, receiving more attention by the National Institutes of Health and various professional societies [5,6].
Improving muscle tone and strength and improving balance are important nonpharmacologic interventions that should be incorporated into the overall management of all osteoporosis patients and, in particular, in patients with CKD. Systemic muscle weakness can be screened by a simple, office-based examination, including hand grip strength and get-up-and-go gait speed (eg, <1 M/second). People who cannot get out of a chair without using their hands have a high risk for falling. Intervention strategies include targeted physical therapy and other core-strengthening modalities and improving balance. (See "Falls: Prevention in community-dwelling older persons".)
TREATMENT OF HYPOGONADISM — In hypogonadal, premenopausal women with chronic kidney disease (CKD), initial management should be directed at the underlying cause. If treatment of hypogonadism is indicated, dosing adjustments are not required in most women with CKD [7]. However, women with G5D kidney disease (table 1) typically require dose adjustments. (See "Evaluation and management of secondary amenorrhea", section on 'Management' and "Evaluation and treatment of premenopausal osteoporosis", section on 'Management'.)
In postmenopausal women, menopausal hormone therapy is generally not considered a first-line option for fracture prevention [8]. Treatment options and the relative benefits and risks of menopausal hormone therapy are reviewed elsewhere. (See "Menopausal hormone therapy: Benefits and risks", section on 'Osteoporotic fracture' and "Menopausal hormone therapy in the prevention and treatment of osteoporosis".)
Hypogonadism is common in men with CKD and estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2 [9-11]. For men with CKD and symptomatic hypogonadism, we administer testosterone therapy (in the absence of contraindications). The dose of testosterone does not need to be adjusted based upon renal function. In men with CKD, observational data suggest that testosterone replacement improves hypogonadal symptoms and anemia [10,11]. In men with normal renal function, testosterone has been shown to improve bone density and muscle mass; however, there are few data demonstrating fracture reduction. (See "Clinical features and diagnosis of male hypogonadism" and "Testosterone treatment of male hypogonadism" and "Treatment of osteoporosis in men", section on 'Congenital hypogonadism'.)
Premenopausal women and men with CKD who are taking hormone replacement therapy may not require additional pharmacologic therapy for osteoporosis.
CANDIDATES FOR PHARMACOLOGIC TREATMENT — The ultimate goal of treating osteoporosis is to prevent fracture. Therefore, selection of patients for pharmacologic therapy for osteoporosis is based upon fracture risk, primarily determined by history of fragility fracture and bone mineral density (BMD), and the presence or absence of chronic kidney disease-mineral and bone disorder (CKD-MBD; eg, adynamic bone disease). CKD-MBD as a cause of fracture or low BMD must be excluded (either through biochemical testing or, if available, bone biopsy) prior to consideration of pharmacologic therapy for osteoporosis. (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation", section on 'Diagnostic evaluation'.)
Our approach outlined below is largely consistent with the 2017 KDIGO (Kidney Disease: Improving Global Outcomes) guidelines [12].
●eGFR ≥30 mL/min/1.73 m2 and no evidence of CKD-MBD – For patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and no evidence of CKD-MBD, the selection of patients for pharmacologic therapy should be the same as for patients without CKD. These criteria are reviewed in detail separately. (See "Treatment of osteoporosis in men", section on 'Patient selection' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Patient selection' and "Evaluation and treatment of premenopausal osteoporosis", section on 'Management'.)
●eGFR <30 mL/min/1.73 m2 or evidence of CKD-MBD
•No history of fragility fracture
-For patients with low BMD, eGFR <30 mL/min/1.73 m2 (or eGFR ≥30 mL/min/1.73 m2 with evidence of CKD-MBD), and no history of a fragility fracture, we suggest not treating with osteoporosis therapy. In patients with evidence of CKD-MBD, management and monitoring of secondary hyperparathyroidism and mineral metabolism abnormalities is necessary. (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)
For patients with eGFR <30 mL/min/1.73 m2, dual-energy x-ray absorptiometry (DXA) alone should not be used for fracture risk assessment [13]. It is unclear if BMD predicts fracture in patients with G4 or G5 CKD (table 1). (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation", section on 'Fracture risk in chronic kidney disease'.)
•History of fragility fracture – Only patients without evidence of renal osteodystrophy on biochemical testing or bone biopsy are candidates for osteoporosis therapy. The use of bone biopsy to exclude renal osteodystrophy (and in particular adynamic bone disease) prior to initiating osteoporosis therapy is at the discretion of the metabolic bone disease specialist and depends upon the availability of a clinician skilled in the performance and interpretation of bone biopsy.
-For patients with an eGFR between 15 and 30 mL/min/1.73 m2 with fragility fracture and without evidence of renal osteodystrophy on biochemical testing (or bone biopsy), we suggest pharmacologic therapy for osteoporosis.
-For patients with an eGFR ≤15 mL/min/1.73 m2 with fragility fracture and without evidence of renal osteodystrophy on bone biopsy, we suggest pharmacologic therapy only when it is clear that the risk of mortality from a recurrent fracture is high (eg, hip fracture) if untreated.
Patients with eGFR ≤15 mL/min/1.73 m2 have a higher incidence of CKD-MBD, and therefore, in this population, we prefer to assess for renal osteodystrophy with bone biopsy (when available) prior to considering antiresorptive therapy. However, if bone biopsy is not feasible, the bone-specific alkaline phosphatase (BSAP) is elevated, and the intact serum parathyroid hormone (PTH) level is >350 pg/mL, adynamic bone disease is unlikely. Treatment with an antiresorptive osteoporosis agent could be considered based upon the biochemical results. (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation", section on 'Bone biopsy'.)
CHOICE OF DRUG
Estimated glomerular filtration rate ≥30 mL/min — Patients with osteoporosis and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 who do not have evidence of CKD-MBD (chronic kidney disease-mineral bone disorder) can be managed similarly, including by use of bisphosphonates, as patients without CKD.
The pharmacologic options for the treatment of osteoporosis in CKD patients with eGFR ≥30 mL/min/1.73 m2 do not differ from those in postmenopausal women and older men without CKD, as long as there are no accompanying biochemical abnormalities (eg, hyperparathyroidism, hyperphosphatemia) that indicate the coexistence of renal osteodystrophy. The efficacy of osteoporosis therapies are similar in these patient groups as evidenced by clinical trials and cohort studies in postmenopausal women or older men, which included subsets of patients who had similar degrees of renal impairment [14-17] (see 'Antiresorptive agents' below). Treatment of adults with osteoporosis is reviewed separately. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy' and "Treatment of osteoporosis in men", section on 'Patient selection' and "Evaluation and treatment of premenopausal osteoporosis", section on 'Management'.)
Estimated glomerular filtration rate <30 mL/min — The challenging clinical issue is how to manage the high-risk or fracturing patient with G4 to G5 or G5D (on dialysis) CKD. There are few data in patients with eGFR between 15 and 30 mL/min/1.73 m2 (G4). Post hoc analyses of trials in postmenopausal women with osteoporosis and G4 CKD showed efficacy and short-term safety of oral bisphosphonates, raloxifene, and denosumab [14,15,18]. (See 'Efficacy' below.)
Bisphosphonates are generally not recommended for those with eGFR below 30 (for alendronate, risedronate, ibandronate) to 35 mL/min/1.73 m2 (for zoledronic acid). They should not be used routinely in patients with an eGFR <30 mL/min/1.73 m2 and should only be considered by clinicians with expertise in CKD-MBD and after biochemical testing and/or bone biopsy (for patients with eGFR <15 mL/min/1.73 m2) exclude renal osteodystrophy.
The basis for the eGFR contraindications include the fact that bisphosphonates are cleared by the kidney (both by glomerular filtration and proximal tubular secretion), that first-generation intravenous (IV) bisphosphonates in older literature have been associated with acute renal failure, and that the clinical trials excluded patients based on specific, prespecified renal measurement cutoffs (either serum creatinine or eGFR) [19,20]. It is known that bisphosphonates are not metabolized and are retained in bone, but it is unknown if there is a greater proportion of bone retention as glomerular filtration rate (GFR) declines. Due in part to these unknowns as well as the unknown implications of greater bone retention of bisphosphonates in patients with impaired renal function, the US Food and Drug Administration (FDA) established a creatinine clearance cutpoint of <35 mL/min/1.73 m2 to avoid bisphosphonate exposure. Hence, bisphosphonate use is not typically recommended, and zoledronic acid is contraindicated in patients with GFR stages G4 to G5 CKD.
Without evidence of CKD-MBD — If there is no biochemical evidence of CKD-MBD (hyperparathyroidism, hyperphosphatemia) and the clinician is certain (based upon biochemical testing [eg, bone-specific alkaline phosphatase (BSAP) is above the upper limit of the laboratory reference range] or bone biopsy) that the type of MBD causing the fracture is not adynamic bone disease, then choices for intervention include oral bisphosphonates (typically contraindicated or not recommended with eGFR <30 to 35 mL/min/1.73 m2, according to bisphosphonate licensing information), denosumab, or raloxifene (for postmenopausal women).
●eGFR 15 to 30 mL/min/1.73 m2 – For patients with eGFR between 15 and 30 mL/min/1.73 m2, some UpToDate experts consider first-line therapy to be an oral bisphosphonate because of decades of clinical experience in this patient population, lower cost, and existing clinical trial data. Other UpToDate experts do not administer bisphosphonates to patients with eGFR <30 to 35 mL/min/1.73 m2. (See 'Efficacy' below.)
If bisphosphonates are administered, the dosing interval and duration should be modified (typically risedronate 35 mg every other week [ie, half the usual dose] and for not more than three years).
Denosumab is an attractive option because it is not cleared by the kidney, but there is limited clinical experience in patients with severe CKD and denosumab administration in hemodialysis patients has been associated with clinically significant hypocalcemia [21-24]. It is unknown whether denosumab influences vascular calcification; information is needed before there is advocacy for widespread administration in patients with eGFR <30 mL/min/1.73 m2. Other therapies for skeletal health, such as raloxifene and calcitonin, are usually not considered in G4 CKD, due to lack of data showing a benefit for reducing nonvertebral fracture risk. In addition, raloxifene increases the risk of thromboembolism.
If an oral bisphosphonate or denosumab is not tolerated, an IV bisphosphonate (typically contraindicated with eGFR <35 mL/min/1.73 m2, according to bisphosphonate licensing information) could be considered in lieu of no treatment, particularly in patients at high risk for recurrent fracture and mortality. In patients with an eGFR <35 mL/min/1.73 m2, clinical experience suggests that using a slower infusion rate (60 minutes) may lower the risk of renal damage [19,25,26]. Treatment should be limited to less than three years and should only be administered by a specialist in CKD-MBD.
●eGFR <15 mL/min/1.73 m2 – Clinical experience is limited, but some experts suggest that in the rare patient with eGFR <15 mL/min/1.73 m2 (G5/5D CKD) whose osteoporotic fracture type is associated with a very high risk of recurrent fracture and mortality, a bisphosphonate or denosumab should be considered instead of no treatment [26-28]. Patients with this degree of renal impairment who fracture should have bone biopsy prior to consideration of osteoporosis therapy. If biopsy does not show evidence of renal osteodystrophy, we prefer an oral bisphosphonate, typically risedronate 35 mg every other week (ie, half the usual dose), and for not more than three years. This lower-dose regimen for risedronate in this specific population is based on the evidence from two separate clinical trials showing that the 2.5 mg/day of risedronate was as effective to reduce vertebral or hip fractures as the approved 5.0 mg/day dose and because risedronate detaches faster from bone surfaces and does not suppress bone remodeling to the same magnitude as other bisphosphonates [29-31]. (See 'Efficacy' below.)
The management of osteoporosis in more severe CKD is a challenge. While more data are needed in this growing population of the aged world, considerations for current pharmacologic therapy should be a thoughtful and open discussion with these patients.
With evidence CKD-MBD — For patients with eGFR between 15 and 30 mL/min/1.73 m2 (G4) or <15 mL/min/1.73 m2 (G5 or G5D) and with evidence of CKD-MBD, antiresorptive osteoporosis drugs should not be administered. There is no evidence for the effectiveness of any antiresorptive treatment to reduce fracture risk in this patient population. The principal goal with regard to bone disease in this setting is to prevent or manage renal osteodystrophy, largely by controlling secondary hyperparathyroidism; preventing oversuppression of PTH, which can lead to adynamic bone disease; and treating acidosis and vitamin D deficiency. Management of secondary hyperparathyroidism is reviewed elsewhere. (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult patients on dialysis".)
Some UpToDate experts consider anabolic agents (eg, parathyroid hormone [PTH]) for patients with history of fragility fracture and low PTH (not medication induced) when there is a high index of suspicion of very low bone turnover or adynamic bone disease [32]. However, this option should only be considered by specialists in CKD-MBD and after biochemical testing and/or bone biopsy (for patients with eGFR <15 mL/min/1.73 m2) evidence of non-iatrogenic adynamic bone disease. (See 'Anabolic agents' below.)
PRETREATMENT EVALUATION — In considering the use of any agent that inhibits bone resorption, particularly one given parenterally where mobilization of calcium from bone is retarded and there may a decline in the serum calcium concentration, serum vitamin D and calcium levels must be assessed prior to administration of bisphosphonates or denosumab. Patients who have hypocalcemia should not receive bisphosphonates or denosumab until hypocalcemia is corrected. Patients with vitamin D deficiency should be replaced with vitamin D prior to administering denosumab. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Pretreatment evaluation' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Calcium and vitamin D supplementation in osteoporosis".)
There have been reports of symptomatic hypocalcemia, especially in patients with G4 to G5 chronic kidney disease (CKD) when given zoledronic acid or denosumab [33,34]. In addition, published data suggest that hypocalcemia may be more common in patients with more severe reductions in glomerular filtration rate (GFR) [24].
The dosing instructions for bisphosphonates and denosumab are reviewed separately. (See 'Without evidence of CKD-MBD' above and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Practical management issues' and "Denosumab for osteoporosis", section on 'Practical management issues'.)
MONITORING THERAPY — Monitoring the response to therapy is important for identifying patients who may require a change in therapy. While there are a number of approaches to monitoring therapy, there is no consensus on the optimal approach.
●eGFR ≥30 mL/min/1.73 m2 – In patients with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, monitoring is similar to patients without chronic kidney disease (CKD). Serial bone mineral density (BMD) measurements are typically performed to assess the clinical response to therapy. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Monitoring response to initial pharmacotherapy' and "Treatment of osteoporosis in men", section on 'Monitoring the response to therapy'.)
●eGFR <30 mL/min/1.73 m2 – In patients with eGFR <30 mL/min/1.73 m2, we measure the following blood tests every four months and also approximately 10 days after denosumab administration:
•Calcium
•Phosphorus
•25-hydroxyvitamin D
•Parathyroid hormone (PTH)
We also measure serum creatinine annually in patients with eGFR <30 mL/min/1.73 m2 who are taking bisphosphonates. For patients on anabolic agents, we measure a serum calcium two weeks after initiation (measured 16 hours or longer after administration) to assess for hypercalcemia.
Patients with CKD (creatinine clearance <30 mL/min, including patients receiving dialysis) are at higher risk for hypercalcemia following calcium and vitamin D supplementation and for hypocalcemia following denosumab administration than patients with normal renal function.
Biochemical markers of bone turnover should not be used to monitor response to therapy in patients with eGFR <30 mL/min/1.73 m2 [35-38].
BMD testing is not routinely performed to assess fracture risk in patients with CKD and eGFR <30 mL/min/1.73 m2 [39] (see "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation", section on 'Bone mineral density: DXA'). However, in select patients with eGFR <30 mL/min/1.73 m2 who have fragility fracture and no evidence of CKD-MBD (mineral and bone disorder), who are initiating osteoporosis therapy, measurement of BMD at baseline and two years after osteoporosis therapy may be helpful for monitoring response to therapy, as it is in patients with eGFR >30 mL/min/1.73 m2. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Monitoring response to initial pharmacotherapy'.)
EFFICACY — There are few data evaluating fracture prevention efficacy and long-term adverse effects of pharmacologic therapy in patients with reduced renal function. In a systematic review of trials evaluating the benefits and harms of osteoporosis medications in patients with chronic kidney disease (CKD), there was insufficient evidence to determine efficacy among patients with G3 to G5 CKD [40].
Osteoporosis clinical trials in men or postmenopausal women included subsets of patients with impaired renal function. While the intent of the osteoporosis trials was to exclude subjects with known renal disease, some participants had a reduced glomerular filtration rate (GFR) simply as a function of the fact that increased age is often accompanied by age-related reduction in GFR [41,42]. Some of these trials are reviewed below.
In all osteoporosis pharmacologic clinical trials, however, patients with elevated baseline serum levels of parathyroid hormone (PTH) were excluded. Thus, there are no clinical trial data examining the efficacy of pharmacologic therapy in patients with evidence of CKD-MBD (mineral bone disorder; ie, with hyperparathyroidism, hyperphosphatemia). Patients with CKD-MBD may also have other abnormalities such as hypocalcemia, high alkaline phosphatase, vascular calcifications, and underlying physiologic abnormalities of bone cell function, such as high fibroblast growth factor 23 (FGF23) or suppressed bone formation.
Antiresorptive agents
Bisphosphonates
●Alendronate and risedronate – Retrospective analyses of the Fracture Intervention Trial (FIT) data and pooled data from nine risedronate studies revealed that 7 to 10 percent of subjects had renal impairment (defined as an estimated glomerular filtration rate [eGFR] <30 to 45 mL/min/1.73 m2) and 37 to 45 percent had moderate impairment (eGFR ≥30 to 59 mL/min/1.73 m2) as estimated by the Cockcroft-Gault formula [14,15]. Compared with placebo-treated women, alendronate and risedronate increased bone mineral density (BMD) and prevented vertebral fracture regardless of degree of renal impairment.
There were no differences in the adverse event rate between patients with normal or reduced renal function in either study. In the FIT study, there was a small increase in creatinine during the three-year study, but the increase was similar in those with and without reduced renal function (mean increase in both groups 0.01±0.10) and in those taking placebo or alendronate. There was no increase in serum creatinine in the risedronate studies (mean exposure of two years).
Thus, oral bisphosphonates appear to be effective in individuals with moderately reduced renal function. However, women with serum creatinine >1.27 mg/dL (112 micromol/L) or serum PTH >85 pg/mL were excluded from participation in FIT, ie, women with renal dysfunction resulting in secondary hyperparathyroidism were not treated with alendronate. Therefore, there are inadequate data with regard to fracture prevention efficacy in those with more severe CKD resulting in secondary hyperparathyroidism and in end-stage renal failure.
●Zoledronic acid – The zoledronic acid (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly [HORIZON]) trials used an eGFR cutoff (<30 mL/min/1.73 m2) for exclusion, rather than a serum creatinine [43]. In post hoc analyses of all of the osteoporosis pharmacologic clinical trials, there are more patients with eGFR <30 mL/min/1.73 m2 in the earlier bisphosphonate trials (alendronate, risedronate, and ibandronate) than in the zoledronic acid clinical trials. Thus, there were too few patients in the zoledronic acid postmenopausal trials with an eGFR below 30 mL/min/1.73 m2 to generate data on use of this intravenous (IV) bisphosphonate in G4 and G5 CKD [43].
In the postmenopausal osteoporosis clinical trials, a small but significant number of patients who received IV zoledronic acid (5 mg) doubled their serum creatinine concentration 9 to 11 days after the 15-minute infusion. In these patients, the serum creatinine returned to baseline before the next annual infusion. It is reassuring that over both the three years of the zoledronic acid trial as well as the six-year extension trial, the eGFR was similar between the patients who received six annual infusions as compared with three annual infusions [44]. However, renal failure is a rare but serious side effect associated with the use of zoledronic acid, particularly in patients with underlying moderate to severe renal impairment [45]. Zoledronic acid is contraindicated in patients with a creatinine clearance <35 mL/min or in patients with evidence of acute renal impairment.
●Ibandronate – Ibandronate is also available in an IV preparation (3 mg IV every three months). However, there are no direct fracture efficacy data for IV ibandronate. While there are no head-to-head studies comparing renal effects of IV zoledronic acid versus IV ibandronate, there are limited data suggesting that the effect of IV ibandronate on eGFR is similar to that of alendronate in postmenopausal women [46]. As an example, in a randomized trial of ibandronate (3 mg every three months administered either as a 15-minute infusion or as an injection given over 15 to 30 seconds) or oral alendronate (70 mg weekly) in postmenopausal women at increased risk for renal disease (eGFR <60 mL/min/1.73 m2, diabetes mellitus, hypertension), there was no significant difference in change in eGFR from baseline among the three groups [46]. Mean eGFR at baseline was approximately 71 mL/min/1.73 m2; a much smaller proportion of patients (n = 46, 5.8 percent) had an eGFR <47 and ≥35 mL/min/1.73 m2.
Denosumab — Denosumab, unlike bisphosphonates, is not cleared by the kidney, and consequently, its use is not restricted in patients with creatinine clearances below 35 mL/min, for whom bisphosphonates are considered contraindicated. However, patients with CKD (creatinine clearance <30 mL/min, including patients receiving dialysis) and/or other conditions that predispose to hypocalcemia are at higher risk for hypocalcemia following denosumab administration than patients with normal renal function. Thus, patients with CKD and creatinine clearance <30 mL/min should be monitored for hypocalcemia. (See "Denosumab for osteoporosis", section on 'Hypocalcemia' and "Denosumab for osteoporosis", section on 'Monitoring'.)
●eGFR ≥15 mL/min/1.73 m2 – The denosumab trials used an eGFR cutoff (<30 mL/min/1.73 m2) for exclusion, rather than a serum creatinine [47]. In a post hoc analysis of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial data, stratified by level of kidney function, denosumab reduced fracture risk and was not associated with an increase in adverse events, including changes in eGFR, among women with impaired kidney function (eGFR ≥30 mL/min/1.73 m2) [48]. Only 73 women had an eGFR of 15 to 29 mL/min/1.73 m2 (G4 CKD), and none had an eGFR <15 mL/min/1.73 m2 (G5). Within the subgroup of women with G4 CKD, too few events (four vertebral and three nonvertebral fractures) occurred to assess fracture prevention. Therefore, data are inadequate for fracture prevention efficacy in those with more severe kidney disease resulting in secondary hyperparathyroidism or late-stage kidney disease (G4). Nevertheless, some evidence supports the effectiveness (improvement in BMD) and safety of denosumab in patients with an eGFR of ≥15 mL/min/1.73 m2 [48].
●eGFR <15 mL/min/1.73 m2 – Limited trial and observational data exist for denosumab use in patients with eGFR <15 mL/min/1.73 m2, including those undergoing dialysis (G5/G5D CKD) [49-52], and no trials have assessed fracture risk reduction. Whereas data collectively support the efficacy of denosumab for increasing BMD and bone strength in such patients [53], concerns persist regarding both hypocalcemia risk and the potential for rapid bone loss after discontinuation of denosumab.
In a trial in 48 patients undergoing hemodialysis who had not received prior osteoporosis pharmacotherapy, one year of treatment with denosumab or alendronate resulted in comparable increases in lumber spine BMD [50]. Neither treatment impacted indices of vascular function including flow-mediated dilation or ankle-brachial pressure index. A subsequent, observational study in 124 patients undergoing dialysis showed progressive increases in areal, cortical volumetric, and trabecular volumetric BMD in the hip over approximately two to three years of denosumab treatment with associated gains in estimated bone strength [52]; however, in a subset of patients in whom denosumab was discontinued (n = 11), all of these parameters declined numerically by one year post-treatment. Further, nine patients developed severe hypocalcemia during denosumab treatment.
Raloxifene — Raloxifene is a less potent antiresorptive agent than bisphosphonates, and therefore, it is used less frequently for the treatment of osteoporosis in postmenopausal women. However, raloxifene is a reasonable alternative to bisphosphonates for postmenopausal women with osteoporosis who are also at high risk for invasive breast cancer. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis", section on 'Raloxifene' and "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Raloxifene'.)
The safety of raloxifene in patients with CKD was evaluated in a post hoc analysis of a randomized trial in which 7705 postmenopausal women with osteoporosis were randomly assigned to raloxifene or placebo [54]. Although women with a serum creatinine of >2.0 mg/dL were excluded from participation in the study, there were 1480 (20 percent) women with an eGFR <45 mL/min/1.73 m2. Among the women with an eGFR <45 mL/min/1.73 m2, 55 had an eGFR <30 mL/min/1.73 m2. Compared with placebo, raloxifene improved BMD and reduced vertebral fractures, irrespective of kidney function. Within each category of kidney function, adverse events were similar between raloxifene and placebo.
In two small, short-term trials, raloxifene was effective in maintaining bone density in patients with G5 and G5D CKD [55,56].
Anabolic agents — The administration of anabolic agents should be limited to patients with biopsy evidence of non-iatrogenic adynamic bone disease and only by specialists in the field of CKD-MBD. (See 'With evidence CKD-MBD' above.)
Teriparatide — PTH (1-34) (teriparatide) is an effective anti-osteoporosis drug that increases BMD and reduces fracture risk by stimulating bone formation (see "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis"). The PTH trials used a serum creatinine concentration of ≤2 mg/dL and a normal serum PTH concentration for inclusion criteria. In a post hoc analysis of the Fracture Prevention Trial, teriparatide had efficacy (improvement in BMD) and safety in patients with eGFR as low as 30 mL/min/1.73 m2 [57]. However, the fracture sample size was limited and only enabled examination of fracture efficacy in subjects with eGFR <80 mL/min/1.73 m2 or >80 mL/min/1.73 m2. The reduction in vertebral and nonvertebral fractures was similar in these two groups. It is important to emphasize that in teriparatide clinical trials (and in all other postmenopausal pharmacologic clinical trials) patients with elevated baseline serum levels of PTH were excluded. Thus, there are no clinical trial data examining the efficacy of teriparatide in patients with evidence of CKD-MBD (hyperparathyroidism, hyperphosphatemia).
Teriparatide may be beneficial in patients with adynamic bone disease [32,58,59]. In a case report, teriparatide (20 mcg by subcutaneous injection daily) was administered to a patient with dialysis-dependent CKD who presented with multiple painful fractures and bone histomorphometry showing low-turnover bone disease [32]. Bone pain resolved within six months, and after 24 months, bone histomorphometry showed improvement in parameters of bone formation. The pharmacokinetics of teriparatide were similar to those observed in postmenopausal women with normal kidney function. Larger studies are needed to assess the role of teriparatide in adynamic bone disease. (See "Adynamic bone disease associated with chronic kidney disease", section on 'Experimental therapies'.)
The teriparatide-induced improvement in parameters of bone formation may be mediated by its effect on sclerostin. Idiopathic renal adynamic bone disease is associated with elevated serum sclerostin, an osteoblast inhibitor. PTH inhibits sclerostin binding to osteoblasts, thereby promoting bone formation [60,61]. Thus, it seems plausible that teriparatide might have value in this population. In addition, the development of monoclonal antibodies to sclerostin, currently in phase III clinical development, might offer a targeted therapy for idiopathic renal adynamic bone disease.
Abaloparatide — Abaloparatide (PTH-related peptide [PTHrP] analogue) is another anabolic agent available for the treatment of osteoporosis [62,63]. Through different mechanisms of action than teriparatide, abaloparatide may have comparable effects to increase bone formation while inducing less bone resorption. Abaloparatide's effect has not yet been examined in patients with GFR <30 mL/min. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Available therapies'.)
Romosozumab — Romosozumab is a monoclonal anti-sclerostin antibody that has been shown to increase bone density and reduce vertebral and nonvertebral fractures. In a retrospective analysis of data from two romosozumab randomized trials (over 11,000 postmenopausal women with osteoporosis, 6299 with mild [eGFR 60 to 89 mL/min/1.73 m2] or moderate [eGFR 30 to 59 mL/min/1.73 m2] kidney impairment), the risk of new vertebral fractures was similarly reduced with romosozumab compared with placebo across eGFR thresholds [64]. Compared with alendronate, the risk of vertebral fractures was reduced similarly in patients with normal kidney function and in those with moderate CKD.
There were no differences in the adverse event rate between patients with normal or reduced renal function in either trial. Romosozumab is an effective treatment to prevent fracture in patients with eGFR ≥30 mL/min/1.73 m2. There are inadequate data with regard to fracture prevention efficacy in those with more severe kidney disease (eg, eGFR <30 mL/min/1.73 m2). (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Romosozumab'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Osteoporosis (The Basics)" and "Patient education: Chronic kidney disease (The Basics)")
●Beyond the Basics (see "Patient education: Osteoporosis prevention and treatment (Beyond the Basics)" and "Patient education: Chronic kidney disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Lifestyle measures – Lifestyle measures, including exercise, cessation of smoking, avoiding excessive alcohol intake, and fall prevention, are important for all patients at high risk for fracture. (See 'Lifestyle measures' above.)
●Calcium and vitamin D supplementation
•eGFR ≥30 mL/min/1.73 m2 – Patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 should have calcium and vitamin D supplementation similar to patients with normal glomerular filtration rate (GFR), as long as there is no biochemical evidence for CKD-MBD (chronic kidney disease-mineral bone disorder; eg, hyperparathyroidism, hyperphosphatemia). (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Optimal intake' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Lifestyle measures to reduce bone loss' and "Treatment of osteoporosis in men", section on 'Lifestyle measures'.)
•eGFR <30 mL/min/1.73 m2 – For patients with an eGFR <30 mL/min/1.73 m2, we suggest calcium and vitamin D supplementation (Grade 2C). The target calcium intake (total diet plus supplement) is 1200 mg/day, with 500 mg/day or less of this total amount provided by calcium supplementation. The difference between the calcium provided by supplementation and total calcium intake should be provided by nutritional means (table 2). In addition, patients should take 800 international units of vitamin D (cholecalciferol or ergocalciferol) daily. (See 'Calcium and vitamin D' above.)
●Treatment of hypogonadism – For hypogonadal, premenopausal women with CKD and low bone mass and/or fragility fracture, we suggest treatment of hypogonadism as initial therapy, rather than osteoporosis pharmacotherapy (Grade 2B). For men with CKD, osteoporosis, and symptomatic hypogonadism, we recommend testosterone therapy (if not contraindicated) (Grade 1B). Premenopausal women and men with CKD who are treated for hypogonadism may not require additional pharmacologic therapy for osteoporosis. (See 'Treatment of hypogonadism' above and "Evaluation and management of secondary amenorrhea" and "Treatment of osteoporosis in men", section on 'Congenital hypogonadism' and "Evaluation and treatment of premenopausal osteoporosis", section on 'Secondary cause identified'.)
●Osteoporosis pharmacologic therapy
•eGFR ≥30 mL/min/1.73 m2 and no evidence of CKD-MBD – For patients with an eGFR ≥30 mL/min/1.73 m2 and no evidence of CKD-MBD, the selection of patients for pharmacologic therapy should be the same as for patients without CKD. (See 'Candidates for pharmacologic treatment' above and "Treatment of osteoporosis in men", section on 'Patient selection' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Patient selection' and "Evaluation and treatment of premenopausal osteoporosis", section on 'Pharmacologic therapy for selected women'.)
For such patients with eGFR ≥30 mL/min/1.73 m2, who do not have evidence of CKD-MBD, and who are candidates for pharmacologic therapy, the choice of pharmacologic therapy is similar as for patients without CKD. Pharmacologic therapy for osteoporosis can be used without change in dosing in patients with G1 to G3 CKD (table 1), recognizing that intravenous (IV) zoledronic acid is contraindicated in patients with a GFR below 35 mL/min/1.73 m2. (See 'Estimated glomerular filtration rate ≥30 mL/min' above and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy' and "Treatment of osteoporosis in men", section on 'Choice of therapy' and "Evaluation and treatment of premenopausal osteoporosis", section on 'Pharmacologic therapy for selected women'.)
•eGFR <30 mL/min/1.73 m2 or with evidence of CKD-MBD, without fragility fracture – For patients with eGFR <30 mL/min/1.73 m2 (or eGFR ≥30 mL/min/1.73 m2 with evidence of CKD-MBD) and low bone mineral density (BMD) without fragility fracture, we suggest not treating with pharmacologic therapy (Grade 2C). For patients with an eGFR <30 mL/min/1.73 m2, dual-energy x-ray absorptiometry (DXA) alone should not be used for fracture risk assessment. There are few data that show BMD predicts fracture in patients with G4 or G5 CKD. (See 'Candidates for pharmacologic treatment' above.)
•eGFR <30 mL/min/1.73 m2 or with evidence of CKD-MBD, with fragility fracture – Patients with an eGFR <30 mL/min/1.73 m2 with a fragility fracture may be candidates for pharmacologic therapy. Such patients require exclusion of other forms of CKD-MBD as a cause of fracture (either through biochemical testing or, if available, bone biopsy) prior to consideration of pharmacologic therapy. (See 'Candidates for pharmacologic treatment' above and "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation", section on 'Diagnostic evaluation'.)
-eGFR 15 to 30 mL/min/1.73 m2 – For fracturing patients with eGFR of 15 to 30 mL/min/1.73 m2 who are candidates for pharmacologic therapy, we suggest an oral bisphosphonate (Grade 2B). Denosumab, which is not cleared by the kidney, is an alternative option. (See 'Choice of drug' above and 'Estimated glomerular filtration rate <30 mL/min' above and 'Without evidence of CKD-MBD' above.)
If an oral bisphosphonate or denosumab is not tolerated, an IV bisphosphonate could be considered in lieu of no treatment, particularly in patients at high risk for recurrent fracture and mortality.
-eGFR <15 mL/min/1.73 m2 – For fracturing patients with eGFR <15 mL/min/1.73 m2 who are candidates for pharmacologic therapy, we suggest an oral bisphosphonate (Grade 2C). We typically prescribe risedronate 35 mg every other week (ie, one-half the usual dose) and for not more than three years. Denosumab is an alternative, although denosumab administration in hemodialysis patients has been associated with clinically significant hypocalcemia. (See 'Estimated glomerular filtration rate <30 mL/min' above and 'Without evidence of CKD-MBD' above.)
-Bisphosphonate precautions – Bisphosphonates should not be used routinely in patients with an eGFR <30 mL/min/1.73 m2 (<35 mL/min/1.73 m2 for zoledronic acid) and should only be considered in such patients by clinicians with expertise in MBD and after excluding renal osteodystrophy. Patients with adynamic bone disease should never be treated with an osteoporosis drug whose mechanism of action is to reduce bone turnover. For fracturing patients with bone biopsy evidence of non-iatrogenic adynamic bone disease, some UpToDate experts will proceed with a trial of an anabolic agent. (See 'With evidence CKD-MBD' above.)
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