Interventions for preventing bone disease in kidney transplant recipients

Suetonia C Palmer; Edmund YM Chung; David O McGregor; Friederike Bachmann; Giovanni FM Strippoli

doi:10.1002/14651858.CD005015.pub4

. 2019 Oct 22;2019(10):CD005015. doi: 10.1002/14651858.CD005015.pub4

Interventions for preventing bone disease in kidney transplant recipients

Suetonia C Palmer ¹, Edmund YM Chung ², David O McGregor ³, Friederike Bachmann ⁴, Giovanni FM Strippoli ^5,^6,^7,^8,^✉

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC6803293 PMID: 31637698

Abstract

Background

People who have chronic kidney disease (CKD) have important changes to bone structure, strength, and metabolism. Children experience bone deformity, pain, and delayed or impaired growth. Adults experience limb and vertebral fractures, avascular necrosis, and pain. The fracture risk after kidney transplantation is four times that of the general population and is related to Chronic Kidney Disease‐Mineral and Bone Disorder (CKD‐MBD) occurring with end‐stage kidney failure, steroid‐induced bone loss, and persistent hyperparathyroidism after transplantation. Fractures may reduce quality of life and lead to being unable to work or contribute to community roles and responsibilities. Earlier versions of this review have found low certainty evidence for effects of treatment. This is an update of a review first published in 2005 and updated in 2007.

Objectives

This review update evaluates the benefits and harms of interventions for preventing bone disease following kidney transplantation.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies up to 16 May 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

RCTs and quasi‐RCTs evaluating treatments for bone disease among kidney transplant recipients of any age were eligible.

Data collection and analysis

Two authors independently assessed trial risks of bias and extracted data. Statistical analyses were performed using random effects meta‐analysis. The risk estimates were expressed as a risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous outcomes together with the corresponding 95% confidence interval (CI). The primary efficacy outcome was bone fracture. The primary safety outcome was acute graft rejection. Secondary outcomes included death (all cause and cardiovascular), myocardial infarction, stroke, musculoskeletal disorders (e.g. skeletal deformity, bone pain), graft loss, nausea, hyper‐ or hypocalcaemia, kidney function, serum parathyroid hormone (PTH), and bone mineral density (BMD).

Main results

In this 2019 update, 65 studies (involving 3598 participants) were eligible; 45 studies contributed data to our meta‐analyses (2698 participants). Treatments included bisphosphonates, vitamin D compounds, teriparatide, denosumab, cinacalcet, parathyroidectomy, and calcitonin. Median duration of follow‐up was 12 months. Forty‐three studies evaluated bone density or bone‐related biomarkers, with more recent studies evaluating proteinuria and hyperparathyroidism. Bisphosphonate therapy was usually commenced in the perioperative transplantation period (within 3 weeks) and regardless of BMD. Risks of bias were generally high or unclear leading to lower certainty in the results. A single study reported outcomes among 60 children and adolescents. Studies were not designed to measure treatment effects on fracture, death or cardiovascular outcomes, or graft loss.

Compared to placebo, bisphosphonate therapy administered over 12 months in transplant recipients may prevent fracture (RR 0.62, 95% CI 0.38 to 1.01; low certainty evidence) although the 95% CI included the possibility that bisphosphonate therapy might make little or no difference. Fracture events were principally vertebral fractures identified during routine radiographic surveillance. It was uncertain whether any other drug class decreased fracture (low or very low certainty evidence). It was uncertain whether interventions for bone disease in kidney transplantation reduce all‐cause or cardiovascular death, myocardial infarction or stroke, or graft loss in very low certainty evidence. Bisphosphonate therapy may decrease acute graft rejection (RR 0.70, 95% CI 0.55 to 0.89; low certainty evidence), while it is uncertain whether any other treatment impacts graft rejection (very low certainty evidence). Bisphosphonate therapy may reduce bone pain (RR 0.20, 95% CI 0.04 to 0.93; very low certainty evidence), while it was very uncertain whether bisphosphonates prevent spinal deformity or avascular bone necrosis (very low certainty evidence). Bisphosphonates may increase to risk of hypocalcaemia (RR 5.59, 95% CI 1.00 to 31.06; low certainty evidence). It was uncertain whether vitamin D compounds had any effect on skeletal, cardiovascular, death, or transplant function outcomes (very low certainty or absence of evidence). Evidence for the benefits and harms of all other treatments was of very low certainty. Evidence for children and young adolescents was sparse.

Authors' conclusions

Bisphosphonate therapy may reduce fracture and bone pain after kidney transplantation, however low certainty in the evidence indicates it is possible that treatment may make little or no difference. It is uncertain whether bisphosphonate therapy or other bone treatments prevent other skeletal complications after kidney transplantation, including spinal deformity or avascular bone necrosis. The effects of bone treatment for children and adolescents after kidney transplantation are very uncertain.

Plain language summary

Interventions for preventing bone disease in kidney transplant recipients

What is the issue?  People who have a kidney transplant can have more fragile bones because of changes to the ways bones are formed in kidney disease and because anti‐rejection medicines including prednisone can make their bones thinner. Bone fractures can cause difficulty with walking and carrying out the activities of everyday living such as work and family life. There are several treatment options for preventing fracture for people with thinner bones but whether these are helpful for kidney transplant patients is not clear. An earlier version of this Cochrane review in 2004 (and updated in 2007) did not find that any of these treatments prevented fractures.

What did we do?

We looked for new studies available since our last review published in 2007 to learn whether there is new information about available treatments for bone disease in people who have had a kidney transplant.

What did we find?  In 2019, there are 65 research studies (involving 3598 people) that looked at whether medicines can prevent bone fractures after kidney transplant. The most common medicine in the studies was a bisphosphonate which slows bone breakdown. Bisphosphonates were given at around the time of kidney transplantation (generally just before or within a few weeks) and continued for about one year on average. Other treatment options in the studies were vitamin D, calcitonin, denosumab, teriparatide, or cinacalcet. Bisphosphonate treatment given after a transplant possibly prevents fractures and bone pain, however the range where the actual effect of treatment might be (the "margin of error") indicates that treatment might make little or no difference. Bisphosphonates possibly lower the chances of a rejection of the transplant kidney but because of problems with the research studies, we can't be very certain that this is true. Bisphosphonates caused low blood calcium levels for some people. There was low or very low confidence in the information about all the other possible treatments for bone fractures after a kidney transplant, as the studies were often too small. There was only one study for medicines in children so we don't know whether these drugs are useful and safe for younger people.

Conclusions  It is still unclear whether bisphosphonate therapy makes any difference to bone fractures or are safe for both adults and children with a kidney transplant.

Summary of findings

Background

Description of the condition

Patient life expectancy after kidney transplantation has improved progressively (Hariharan 2001). Attention is increasingly focused on preventing the longer‐term complications of transplantation and improving quality of life by addressing factors that affect long‐term morbidity including cardiovascular risk, weight gain, post‐transplantation diabetes mellitus, cancer, and bone disease. The bone disease that develops after kidney transplantation is an important cause of complications including fracture, pain, deformity, and disability. The bone disease that accrues after transplantation is the pathological intersection of several processes including Chronic Kidney Disease Mineral and Bone Disorder (CKD‐MBD) due to long‐term kidney failure, bone metabolic changes related to transplant immunosuppression (particularly corticosteroids), and persistently impaired kidney function leading to ongoing raised parathyroid gland activity (Malluche 2010). The resulting pathobiology of the bone includes altered bone mineralization and bone turnover, reduced bone volume, and increased fragility related to altered bone tissue and architecture. Increased circulating levels of fibroblast growth factor 23 (FGF23) may persist after transplantation leading to hypophosphataemia and hypercalcaemia in the short term, and are associated with allograft dysfunction and mortality in the longer term (Wolff 2011).

Patients with chronic kidney disease (CKD) are at increased risk for fracture, with a vertebral fracture prevalence of 21% and relative risk (RR) for hip fracture increased up to 14‐fold (Sprague 2004). The fracture risk for kidney transplant recipients is four times that of the general population and is increased when compared with haemodialysis patients (Grotz 1994; Veenstra 1999). Studies report a fracture prevalence of 7% to 60% (Durieux 2002; Giannini 2001; Monier‐Faugere 2000; Nisbeth 1999; O'Shaunessy 2002; Vautour 2004) following successful kidney transplantation with an incidence of 2% per year (Abbott 2001; Grotz 1994). Women, patients with diabetes, those with an increased duration of dialysis therapy, older patients, and people who have experienced a longer time since transplantation have a higher risk (Sprague 2004). Recipients of a kidney transplant lose bone rapidly and early following transplantation (Almond 1994; Horber 1994; Julian 1991) from sites rich in trabecular bone. Bone mineral density (BMD) decreases in the lumbar spine by 5% in the first year after transplantation (Torregrosa 2003) and longitudinal studies in stable kidney transplant recipients demonstrate bone loss of 1.7% annually at the lumbar spine (Pichette 1996). Beyond three years after transplantation BMD does not change or may increase slightly but remains below values for the normal population (Grotz 1995). Fractures may occur early and affect patients with both low and normal BMD.

Immunosuppressive agents used in solid organ transplantation exert protean effects on bone metabolism (Torres 2002). Bone formation and mineralization lag times may be prolonged, suggesting an imbalance between bone formation and resorption because of osteoblastic dysfunction (Monier‐Faugere 2000). Glucocorticoids cause a substantial loss of trabecular bone in the initial months of treatment (Sambrook 1988), decrease calcium absorption and urinary calcium excretion, and exacerbate secondary hyperparathyroidism (Hahn 1981). Data regarding the effects of cyclosporin on bone function are conflicting although evidence suggests cyclosporin may contribute independently to lowered bone density following kidney transplantation (Heaf 2000). The roles of tacrolimus and sirolimus on bone metabolism do not extend beyond animal studies.

Description of the intervention

A number of agents are proven to treat and prevent osteoporosis in non‐transplant populations. Bisphosphonates, through their antiresorptive properties, are efficacious in the treatment steroid‐induced osteoporosis (Adachi 1997). Vitamin D metabolism is disturbed before and after kidney transplantation where half of patients show low blood levels of 1,25 dihydroxyvitamin D until six months after transplantation (De Sevaux 2002). Active vitamin D compound and calcium supplementation during this time reduces bone loss (Jeffery 2003). A meta‐analysis suggested 1,25 dihydroxyvitamin D (active vitamin D3, calcitriol) supplementation following kidney transplantation may be more efficacious in preventing vertebral fractures compared with no treatment, placebo or other vitamin D sterols with or without calcium supplementation (De Nijs 2004). Calcitonin has been proven to prevent recurrence of osteoporotic fractures in women with established osteoporosis (Chesnut 2000; Karachalios 2004) but data in patients receiving renal replacement therapy are absent. Following kidney transplantation female gender and post‐menopausal status are associated with an exaggerated risk of bone loss (Hung 1996). In non‐transplant populations, combined hormone replacement therapy has been shown to increase BMD in post‐menopausal osteoporosis (Grey 1994) and testosterone treatment reverses the deleterious effects of glucocorticoid drugs on bone mass in men (Reid 1996). The impact of gonadal hormone replacement following kidney transplantation is not characterised.

More recently denosumab, through inhibition of RANK ligand (RANKL)‐mediated osteoclast activation, has shown to be effective in the treatment of osteoporosis (Cummings 2009),with an equivalent efficacy to bisphosphonate (Brown 2009). Teriparatide, a recombinant parathyroid hormone (PTH), has proved to be efficacious in osteoporosis of both postmenopausal women (Neer 2001) and men (Orwoll 2003). Cinacalcet is a calcimimetic agent that has been shown to reduce intact PTH levels in patients with secondary hyperparathyroidism in the setting of CKD (Chonchol 2009), which may persist post‐kidney transplantation and contribute to osteoporosis. However, the efficacy of these agents in the treatment and prevention of osteoporosis in renal transplant recipients is largely unproven.

How the intervention might work

Bone loss occurs rapidly in the first 6 to 12 months after kidney transplantation. Contributing factors include pre‐existing bone disease related to kidney failure, immunosuppressive drugs, PTH activity, low serum phosphorus, and kidney transplant function (Weisinger 2006). In the absence of specific agents for the treatment and prevention of osteoporosis in the setting of CKD and post‐renal transplantation, treatments that have been proven in non‐transplant populations have been used to prevent and treat bone disease among kidney transplant recipients. The available drugs include bisphosphonate, vitamin D compounds, cinacalcet, calcitonin, testosterone, selective oestrogen receptor modulators, receptor activator of NF‐ĸB ligand (RANKL) inhibitors, synthetic human PTH, and treatments for acidosis such as potassium salts. Bone undergoes constant turnover; homeostasis is maintained through the balance of osteoblast activity (cells that generate bone matrix) and osteoclasts (cells that break down bone matrix). Each treatment acts on this complex bone remodelling process to either slow bone resorption or increase bone formation. Bisphosphonates inhibit osteoclast function by increasing programmed cell death (apoptosis); vitamin D compounds regulate circulating calcium and phosphorus concentrations and impacts on bone remodelling though increased bone resorption; RANKL inhibitors decrease RANKL‐induced osteoclast formation; synthetic human PTH increases the number and activity of osteoclasts; selective oestrogen receptor modulators (SERMs) act via the human transforming growth factor‐β3 gene, which regulates bone remodelling; cinacalcet mimics the action of calcium on tissues via activation of the calcium‐sensing receptors, increasing the sensitivity of calcium receptors on parathyroid cells to reduce PTH levels; calcitonin inhibits osteoclast activity and stimulates osteoblast activity; chronic acidosis changes the ionic composition of bone with reduced apatite, sodium and potassium and matrix gene expression with inhibition of osteoblast activity and increased osteoclastic function.

Why it is important to do this review

The wide variability in the causes of bone loss after kidney transplantation (low or high bone turnover, altered PTH function, steroid‐induced bone changes) suggests the possibility that treatments effective for osteoporosis in the wider population may not be directly applicable to the specific setting of kidney transplantation. In addition, treatments may exacerbate low bone turnover and increase complications of bone fragility and loss. Specialist guidelines regarding treatment of bone disease in kidney transplantation were previously based on uncontrolled data (Table 3 ‐ Published guidelines for bone disease in kidney transplant recipients) but randomised data is emerging specific to the treatment of bone disease in solid organ transplantation including among kidney transplant recipients. This Cochrane review update includes studies conducted during or before 2019 to determine the benefits and harms of treatments for bone disease in adults and children who have a kidney transplant and to identify areas requiring further study.

1. Published guidelines for bone disease in kidney transplant recipients.

Guideline	Country	Year	Recommendation
Kidney Disease: Improving Global Outcomes (KDIGO) 2009 Clinical Practice Guideline for CKD Mineral and Bone Disorder (CKD‐MBD) (KDIGO CKD‐MBD Guideline 2009)	International	2009	Serum concentrations of calcium, phosphorous and intact PTH should be monitored following transplantation. Serial 25(OH) vitamin D measurements should be considered. The lowest effective dose of glucocorticoids should be used. Recommend vitamin D deficiency and insufficiency be corrected. BMD measurement by DEXA scan is suggested within the first 3 months of transplantation if eGFR > 30 mL/min/1.73 m² and patient is on corticosteroids or have risk factors for osteoporosis. In the first 12 months post transplantation, if eGFR > 30 mL/min/1.73 m² and low BMD, suggest vitamin D, calcitriol/alpha calcidiol, or bisphosphonate be considered. Insufficient data to guide treatment after the first 12 months. Suggest BMD testing not performed routinely as BMD does not predict fracture risk or the type of transplant bone disease.
Kidney Disease: Improving Global Outcomes (KDIGO) 2009 Clinical Practice Guideline for the Care of Kidney Transplant (KDIGO Transplant Guideline 2009)	International	2009	See Kidney Disease: Improving Global Outcomes (KDIGO) 2009 Clinical Practice Guidelines for CKD Mineral and Bone Disorder (CKD‐MBD) (KDIGO CKD‐MBD Guideline 2009)
Kidney Disease Outcome Quality Initiative (K‐DOQI) (KDOQI 2010)	United States of America	2010	Commentary on 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD‐Mineral and Bone Disorder (CKD‐MBD) Serum concentrations of calcium, phosphorous and intact PTH should be monitored following transplantation. Serial 25(OH) vitamin D measurements should be considered. The lowest effective dose of glucocorticoids should be used. Recommend vitamin D deficiency and insufficiency be corrected. BMD measurement by DEXA scan is restricted to high risk populations including those receiving significant doses of corticosteroids or those with risk factors for osteoporosis in the general population. Bone density screening is suggested only for individuals with a well‐functioning transplant. Patients with more advanced CKD will more likely have abnormal bone quality from CKD mineral and bone disorder which is likely to compromise the ability of BMD to predict fracture. In the first 12 months post transplantation, if eGFR > 30 mL/min/1.73 m² and low BMD, suggest vitamin D, calcitriol/alpha calcidiol, or bisphosphonate be considered, although due to the relative lack of evidence, treatment is discretionary. Insufficient data to guide treatment after the first 12 months. There is insufficient evidence to support treatment recommendations for bone disease in children. It is reasonable to consider bone biopsy to guide treatment, particularly before using bisphosphonate because these agents have better efficacy in high bone turnover and may lead to adynamic bone disease.
Caring for Australians with Renal Impairment (CARI) (Chadban 2009)	Australia and New Zealand	2009	Kidney transplant recipients should be advised to take a vitamin D (or analogue) supplement at a low dose of at least 0.25 µg daily. Commentary on 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients No specific comment on 2009 KDIGO guidelines for care of kidney transplant recipients.
Canadian Society of Nephrology (CSN) (Knoll 2010)	Canada	2010	Commentary on 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant recipients No evidence for benefit resulting from supplementation to "sufficient" levels of serum 25 hydroxyvitamin D (> 75 nmol/L) and the clinical harm has not been defined. Bone biopsy is rarely available. In patients who have no biochemical evidence of CKD bone and mineral disorder, it is reasonable to assess and treat patients for their future fracture risk according to guidelines for the general population. management would include routine supplementation with vitamin D (800 to 2,000 U daily) and calcium (1000 to 15,000 mg daily) with specific pharmacotherapy based on overall risks of fracture, including bisphosphonate therapy when appropriate. Bone density should not be measured routinely to form the basis of diagnostic and therapeutic decisions.
European Best Practice Guidelines (EPBG) (ERBP 2011)	Europe	2011	Endorsement of the 2009 KDIGO Clinical Practice Guideline for Care of Kidney Transplant Recipients Endorsement of the 2009 KDIGO guidelines for care of kidney transplant recipients (KDIGO CKD‐MBD Guideline 2009) (no specific commentary on bone disease management).
British Renal Association (Baker 2010)	United Kingdom	2010, 2011	Post‐operative care of the kidney transplant recipient: bone and joint disease (Baker 2017) Recipients of kidney transplantation with osteoporosis or high risk should be considered for steroid‐avoiding immunosuppression. Recipients of a kidney transplant should undergo bone density measurement if eGFR > 30 mL/min/1.73 m². Treatment should be according to the Royal College of Physicians guidelines for steroid induced osteoporosis. Commentary on 2009 KDIGO Clinical Practice Guideline for the Care of Kidney Transplant recipients The recommendations on transplant bone disease are derived from the KDIGO guideline on the diagnosis, evaluation, prevention and treatment of Chronic Kidney Disease‐Mineral and Bone Disorder (CKD‐MBD). The widespread use of DEXA scanning is not recommended since it predicts neither the occurrence of fractures nor the type of bone disease.

Study	Donor	Primary outcome	Intervention	Dose	Timing since transplantation	Duration of treatment or follow up	Risk factors for fracture in participant selection criteria (exclusions)
Bisphosphonates (in order of drug potency from low to high)
Psimenou 2002 (adults)	‐‐	BMD	Etidronate	200 mg/d for 15 days every 3 months	‐‐	12 months	Low BMD; mean T‐scores < ‐2.7 at baseline (no exclusions specified)
Grotz 1998 (adults)	‐‐	BMD	Clodronate	800 mg/d	> 6 months	12 months	BMD < 1.5 SD of normal; > 6 months after transplantation (no exclusions specified)
Montilla 2001 (adults)	‐‐	BMD	Pamidronate	200 mg twice/d	‐‐	12 months	Long‐term kidney transplant recipients with severe osteopenia or osteoporosis (no exclusions specified)
Fan 2000 (men)	Deceased	BMD	Pamidronate	0.5 mg/kg at time of transplantation and 1 month	Immediately pre‐transplant	12 months	No risk factors specified. Incident population (women excluded)
Nam 2000 (adults)	‐‐	BMD	Pamidronate	30 mg every 4 weeks	2 weeks	6 months	No risk factors specified. Incident population (no exclusions specified)
Coco 2003 (adults)	Living and deceased	Bone histomorphometry and BMD	Pamidronate	60 mg at transplantation and 30 mg at 1, 2, 3 and 6 months	48 hours	12 months	No risk factors specified. Incident population (excluded if unstable transplant function)
Walsh 2009 (adults)	‐‐	BMD	Pamidronate	1 mg/kg within 14 to 19 days of transplant, 1, 4, 8, 12 months after transplant	< 14 to 19 days	12 months	Serum PTH level > 150 pg/mL (no exclusions specified)
Torregrosa 2011 (adults)	‐‐	BMD	Pamidronate	30 mg between day 7 to 10 and 3 months	5 to 7 days	12 months	T‐score < ‐1 at lumbar spine. (excluded if CrCl < 30 mL/min; corticosteroids > 3 months before transplantation)
Sirsat 2010 (adults)	‐‐	BMD	Pamidronate	60 mg at baseline and 6 months post transplant	‐‐	1 year	Kidney transplant recipients (no exclusions reported)
Shahidi 2015 (adults)	Living	BMD	Pamidronate	30 mg within 2 days and at 3 months	< 2 days	12 months	No risk factors specified. Incident population (excluded if previous parathyroidectomy; corticosteroids > 3 months duration before transplantation)
Omidvar 2011 (adults)	‐‐	BMD	Alendronate or pamidronate	70 mg/week; 90 mg/month	3 weeks	6 months	T‐score < ‐2 (excluded if history of hyperparathyroidism, hypocalcaemia, hypercalcaemia; fracture within 2 years; CrCl < 35 mL/min)
Giannini 2001 (adults)	Deceased	BMD and bone biomarkers	Alendronate	10 mg/d	> 6 months	12 months	> 6 months after transplantation. Deceased donor kidney (excluded if antiresorptive drugs or bisphosphonate therapy)
Koc 2002 (adults)	‐‐	BMD	Alendronate	10 mg/d	46.2 months on average	12 months	Long‐term transplantation (46.2 months average) (excluded if diabetes; hyperparathyroidism; gonadal insufficiency; parathyroidectomy; other cause of osteoporosis)
Sharma 2002a (adults)	‐‐	BMD	Alendronate	10 mg/d	At time of transplantation	6 months	No risk factors specified. Incident population (no exclusions specified)
El‐Agroudy 2003a (men)	Living	BMD	Alendronate	5 mg/d	< 1 week	12 months	No risk factors specified. Incident population (excluded if diabetes; steroids received before transplantation; HD > 2 years; SCr > 2 mg/dL; previous fractures; presence of other endocrine abnormalities)
Jeffery 2003 (adults)	Living and deceased	BMD	Alendronate	10 mg/d	8.5 to 9 years	12 months	T‐score ≤ ‐1 (excluded if CrCl < 35 mL/min; unstable kidney function; hormonal replacement therapy; treated for symptomatic osteoporosis)
Torregrosa 2003 (adults)	‐‐	BMD	Alendronate	10 mg/d	12 to 24 months	12 months	T‐score < ‐2.5; SCr < 176.8 µmol/L; PTH < 240 pg/mL (excluded if diabetes)
El‐Husseini 2004 (children and adolescents)	Living	BMD	Alendronate	5 mg/d	48 months on average	12 months	T‐score ≤ ‐1; SCr < 220 mmol/L (no exclusions specified)
Nayak 2007 (adults)	‐‐	BMD	Alendronate	35 mg/week	After stabilization of kidney function	6 months	No risk factors specified. Incident population (excluded if bone disease or long‐term immunosuppressive therapy before onset of kidney failure)
Lan 2008 (adults)	‐‐	BMD and bone biomarkers	Alendronate	70 mg/week	> 12 months	6 months	T‐score < ‐1; >1 year after transplantation (excluded if diabetes; liver disease; intake of vitamin D or analogues after transplantation)
Sirsat 2010 (adults)	‐‐	BMD	Alendronate	70 mg/week	‐‐	1 year	Kidney transplant recipients (no exclusions specified)
Trabulus 2008 (adults)	Living and deceased	BMD	Alendronate or alendronate + alfacalcidol	10 mg/d ± 0.5 µg/d	37.3 to 49.7 months on average	12 months	SCr < 124 µmol/L (excluded if post‐menopausal; oestrogen therapy; osteoporosis secondary to diabetes; hyperthyroidism; primary or tertiary hyperparathyroidism; hypogonadism; hyperprolactinaemia; Cushing's syndrome; acromegaly; diarrhoea; malabsorption syndromes)
Dovas 2009 (adults)	‐‐	BMD	Alendronate + alfacalcidol	70 mg weekly + 0.25 µg alternate daily	At transplantation	24 months	Unselected patients (no exclusions specified)
Okamoto 2014 (adults)	‐‐	BMD and vascular calcification score	Alendronate	35 mg/week	> 12 months (mean 45.3 to 59.6 months)	24 months	SCr < 176 µmol/L; stable graft function (no exclusions specified)
Lord 2001a (adults)	‐‐	Fracture, BMD	Alendronate + Vitamin D + calcium	5 mg/d	‐‐	2 years	Kidney transplant recipients (excluded if aged 18 years (?); more than 1 kidney transplant; severe hyperparathyroidism or osteoporosis)
Nakamura 2009a (adolescents and adults)	‐‐	BMD	Alendronate	‐‐	‐‐	6 to 12 months	Kidney transplant recipients > 16 years with good kidney function (no exclusions specified)
Grotz 2001 (adults)	‐‐	BMD	Ibandronate	1 mg before transplantation and 2 mg at 3, 6, and 9 months	Immediately pre‐transplant	12 months	No risk factors specified. Incident population (excluded combined kidney pancreas transplant recipients)
Smerud 2012 (adults)	Living or deceased	BMD	Ibandronate	3 mg every 3 months	18.5 days on average	12 months	Stable kidney function (eGFR > 30 mL/min/1.73 m²; plasma calcium < 2.55 mmol/L). Incident population (excluded if adynamic bone disease; previous parathyroidectomy, use of bisphosphonate within previous 1 year; medications including sodium fluoride; calcitonin; strontium; PTH; selective oestrogen receptor modulators; growth hormone; anabolic steroids)
Sanchez‐Escuredo 2015 (adults)	‐‐	BMD	Risedronate or ibandronate	35 mg/week or 150 mg/month	> 12 months (mean 18 to 20 months)	12 months	Minimum 12 months after transplantation. Serum PTH > 60 pg/mL; T‐score < 1; CrCl > 30 mL/min/1.73 m² (excluded if diabetes; primary hyperthyroidism)
Coco 2012 (adults)	Living	BMD	Risedronate	35 mg dose	Given when SCr < 2.0 mg/dL after transplantation	12 months	Living donor transplantation. Incident population (no exclusions specified)
Torregrosa 2007 (adults)	‐‐	Fracture, pain, and BMD	Risedronate	35 mg/week	12 to 36 months (21 to 23 months)	12 months	T‐score < ‐1; SCr < 221 µmol/L; iPTH > 60 pg/mL (excluded if diabetes)
Torregrosa 2010 (adults)	‐‐	BMD	Risedronate	35 mg/week	At time of transplantation	12 months	No risk factors specified. Incident population (excluded if insulin treatment; parathyroidectomy; fluorine, bisphosphonate, hormone therapy (oestrogen, selective modulator of oestrogen receptor), calcitonin therapy; PTH < 50 pg/mL)
Fujii 2006 (adults)	‐‐	BMD	Risedronate	2.5 mg/d	11 ± 6 years	2 years	Long‐term kidney transplant recipients; eGFR 64 ± 31 mL/min/1.73 m²; T‐score of ‐2.0 ± 0.9 at the lumbar spine (no exclusions specified)
Haas 2003 (adults)	Deceased	BMD	Zolendronate	4 mg at 0 and 3 months	< 2 weeks	6 months	Deceased donor transplantation. Incident population (excluded if treatment with calcitonin, bisphosphonate; hypocalcaemia)
Vitamin D
Marcen 2010 (unknown)	‐‐	iPTH	Cholecalciferol + calcium supplements	400 IU/d	‐‐	6 to 12 months	Kidney transplant recipients with vitamin D insufficiency or deficiency (no exclusions reported)
Thervet 2008 (unknown)	‐‐	PTH	Cholecalciferol	100,000 U every 2 months initiated 4 months post transplant	4 months	12 months	Kidney transplant recipients; vitamin D < 30 ng/mL; calcium < 35 mmol/L (no exclusions specified)
Thervet 2008 (unknown)	‐‐	PTH	Cholecalciferol	100,000 U every 2 months initiated 6 months post transplant	6 months	12 months	Kidney transplant recipients; vitamin D < 30 ng/mL; calcium < 35 mmol/L (no exclusions specified)
Wissing 2005 (adults)	Living and deceased	BMD	Vitamin D3	25,000 IU/month	1 week	12 months	No risk factors specified. Incident population (excluded if serum calcium > 10.5 mg/dL; hypocalcaemia requiring treatment with active vitamin D compounds; multiorgan transplant)
Tałałaj 1996 (adults)	‐‐	BMD	25‐hydroxy vitamin D and calcium carbonate	40 µg/d; 3000 mg/d	25 to 26 months	12 months	No risk factors specified (no exclusions specified)
Praditpornsilpa 2014 (unknown)	‐‐	iPTH	Calcidiol	20,000 IU/week	‐‐	‐‐	Kidney transplant recipients (no exclusions specified)
De Sevaux 2002 (adults)	Living and deceased	BMD	1‐alpha‐hydroxy vitamin D + calcium	0.25 µg/d 1000 mg/d	< 1 month	6 months	No risk factors specified. Incident population (excluded if corticosteroid treatment within 3 months of transplantation; total parathyroidectomy; treatment with bisphosphonates, fluoride, calcitonin, or anabolic steroids; serum calcium >2.80 mmol/L)
El‐Agroudy 2003a (men)	Living	BMD	Alfacalcidol	0.5 µg/d	< 1 week	12 months	No risk factors specified. Incident population (excluded if diabetes; steroids received before transplantation; HD > 2 years; SCr > 2 mg/dL; previous fractures; presence of other endocrine abnormalities)
El‐Husseini 2004 (children and adolescents)	Living	BMD	Alfacalcidol	0.25 µg/d	48 months on average	12 months	T‐score ≤ ‐1 (excluded if anticonvulsant therapy or thiazide diuretic treatment)
El‐Husseini 2005a (children and adolescents)	‐‐	BMD	Alfacalcidol	0.25 µg/d	‐‐	12 months	Kidney transplant recipients with low BMD (Z‐score ≤ ‐1) (no exclusions reports)
Trabulus 2008 (adults)	Living and deceased	BMD	Alfacalcidol	0.5 µg/d	37.3 to 49.7 months on average	12 months	SCr < 1.4 mg/dL; stable graft function (excluded if post‐menopausal, oestrogen therapy; secondary osteoporosis due to type I or II diabetes; hyperthyroidism; hypogonadism; hyperprolactinaemia; Cushing's syndrome; acromegaly; chronic diarrhoea; malabsorption syndrome)
Nakamura 2009a (adolescents and adults)	‐‐	BMD	Alfacalcidol	‐‐	‐‐	6 to 12 months	Kidney transplant recipients > 16 years with good kidney function (no exclusions specified)
Shahidi 2011 (adults)	‐‐	BMD	Calcitriol or vitamin D	‐‐	Immediately prior to transplantation	12 months	Inclusion and exclusion criteria not reported in abstract
Neubauer 1984 (adults)	Deceased	Bone mineral content	Calcitriol	0.25 µg/d	8 weeks	18 months	Deceased donor transplantation. Incident population (excluded if SCr > 1.8 mg/dL; hypercalcaemia; systemic disease)
Eid 1996 (women)	‐‐	BMD	Calcitriol	0.25 µg/d	Not described	36 months	Post‐menopausal women (no exclusions specified)
Messa 1999 (adults)	‐‐	Serum PTH	Calcitriol	0.008 µg/kg/d	At transplantation	6 months	Kidney transplantation (no exclusions specified)
Tiryaki 2015 (adults)	‐‐	Albuminuria	Calcitriol	0.25 mg/d	‐‐	24 weeks	Hypertension; chronic allograft nephropathy; albuminuria (no exclusions specified)
Cueto‐Manzano 2000 (adults)	Living and deceased	BMD	Calcitriol + calcium carbonate	0.25 µg/d 500 mg/d	> 2 years	12 months	Kidney transplantation > 2 years; stable graft function; SCr <2.0 mg/dL; normal dietary intake (excluded if previous vertebral or hip fracture; prolonged immobilisation; systemic illness; malignancy; oestrogen therapy; drugs affecting bone metabolism)
Nam 2000 (adults)	‐‐	BMD	Calcitriol	0.5 µg/d	2 weeks	6 months	Incident population (no exclusions specified)
Ugur 2000 (adults)	‐‐	BMD	Calcitriol	0.5 µg/d	> 12 months	12 months	T‐score < ‐1; transplantation > 12 months (no exclusions specified)
Giannini 2001 (adults)	Deceased	BMD	Calcitriol	0.25 µg/d	> 6 months	12 months	Deceased donor transplantation; kidney transplantation > 6 months (excluded if previous treatment with bisphosphonates or other antiresorptive drugs)
Koc 2002 (adults)	‐‐	BMD	Calcitriol	0.5 µg/d	< 12 months	12 months	Long‐term transplantation (46.2 months average) (excluded if diabetes; hyperparathyroidism; gonadal insufficiency; parathyroidectomy; other cause of osteoporosis)
Torres 2004 (adults)	‐‐	BMD	Calcitriol	0.5 µg/48 hours	At time of transplantation	12 months	First or second kidney transplant (excluded is previous parathyroidectomy)
Arnol 2011 (adults)	‐‐	Proteinuria	Paricalcitol	2 µg/d	≥ 3 months	24 weeks	Kidney transplant > 3 months; UPCR ≥ 20 mg/mmol (no exclusions specified)
Kharlamov 2012 (adults)	Deceased	Chronic allograft nephropathy	Paricalcitol or calcitriol or vitamin D supplement	2‐4 µg/d 1 to 6 µg/d 1200 to 1800 IU	Day 5 after transplant	6 months	Vitamin D deficiency (25(OH)D < 40 nmol/L) (excluded if acute illness; endocrinologic disease including diabetes; hyperparathyroidism; other thyroid disorders; need for dialysis)
Oliden 2012 (adults)	Living and deceased	PTH	Paricalcitol versus calcitriol	2 µg/d 0.25 mg/d	50 to 120 months	24 weeks	GFR < 60 mL/min; secondary hyperparathyroidism (excluded if PTH < 110 pg/mL; corrected calcium > 10.5 mg/dL; serum phosphorus > 5.5 mg/dL)
Amer 2013 (adults)	Living and deceased	PTH	Paricalcitol	2 µg/d	At transplantation	12 months	First or second kidney transplant; eligible for steroid avoidance protocol (excluded if prior hypercalcaemia; total 25‐hydroxyvitamin D < 10 ng/mL; multiple organ transplant; receiving calcimimetic before transplant)
Perez 2010 (adults)	‐‐	Bone mineral parameters, kidney function and inflammatory markers	Paricalcitol	1 µg/d	‐‐	12 months	Stable kidney transplant (no exclusions specified)
Trillini 2015 (adults)	‐‐	PTH	Paricalcitol	1 to 2 µg/d	92.2 months on average	6 months	Serum PTH > 80 pg/mL; 1‐month washout with previous vitamin D compounds; serum calcium ≤ 10.2 mg/dL; SCr < 2 mg/dL (excluded if vitamin D analogue therapy; changes in SCr > 30%; acute rejection episode over previous 6 months)
Pihlstrom 2017 (adults)	Living and deceased	Albuminuria	Paricalcitol	2 µg/d	7 to 8 weeks	44 weeks	Kidney transplant or combined kidney‐pancreas transplant; eGFR > 30 mL/min; plasma calcium 2.0 to 2.6 mmol/L (excluded previous total parathyroidectomy; ongoing treatment with vitamin D, VDRA, or calcimimetic drugs; severe osteoporosis in axial skeleton; donor age > 75 years)
Lord 2001a (adults)	‐‐	Fracture, BMD	Vitamin D + calcium	‐‐	‐‐	2 years	Kidney transplant recipients (excluded if aged 18 years (?); more than 1 kidney transplant; severe hyperparathyroidism or osteoporosis)
RANKL inhibitor
POSTOP 2014 (adults)	Living and deceased	BMD	Denosumab	60 mg at baseline and 6 months	2 weeks	12 months	Incident population (excluded if T‐score < ‐4; severe hypo‐ or hyperparathyroidism (iPTH > 800 or <10 mg/L; total calcium < 1.8 or > 2.7 mmol/L)
Recombinant PTH
Cejka 2008 (adults)	Deceased	BMD and histomorphometry	Teriparatide	20 µg/d	1 month	6 months	Deceased donor transplantation; SCr < 2 mg/dL. Incident population (excluded if DGF; persistent severe hyperparathyroidism (reduction of < 50% in post‐transplant PTH levels with either biopsy‐proven high‐turnover renal bone disease or pre‐transplant concentration > 300 pg/mL); hypercalcaemia)
Calcimimetic
Evenepoel 2014 (adults)	‐‐	Serum calcium	Cinacalcet	30 to 180 mg/d	9 weeks to 24 months	12 months	First or second kidney transplant; stable kidney function (eGFR ≥ 30 mL/min/1.73 m²; corrected serum calcium > 10.5 mg/dL; iPTH > 100 pg/mL (excluded if continued use of bisphosphonates; vitamin D analogues; calcium supplements; phosphate binders or thiazide diuretics)
Pasquali 2014 (adults)	‐‐	Serum calcium	Cinacalcet versus paricalcitol	Mean 41 ± 15 mg/d	7 ± 5 years	3 months	Kidney transplant recipient with secondary hyperparathyroidism, response to cinacalcet therapy (based on lowered serum calcium) (no exclusions specified)
Cruzado 2015 (adults)	‐‐	Serum calcium	Cinacalcet	30 mg/d titrated	≥ 6 months	12 months	eGFR ≥ 30 mL/min/1.73 m²; 6 months or longer since transplantation; serum PTH ≥ 15 pmol/L; total serum calcium ≥ 2.63 mmol/L; serum phosphorus ≤ 1.2 mmol/L (no exclusions specified)
Parathyroidectomy
Cruzado 2015 (adults)	‐‐	Serum calcium	Parathyroidectomy	‐‐	≥ 6 months	12 months	eGFR ≥ 30 mL/min/1.73 m²; 6 months or longer since transplantation; serum PTH ≥ 15 pmol/L; total serum calcium ≥ 2.63 mmol/L; serum phosphorus ≤ 1.2 mmol/L (no exclusions specified)
Hormone replacement therapy
Eid 1996 (women)	‐‐	BMD	β‐estradiol and medroxyprogesterone	50 µg/d 10 mg/d	Not described	36 months	Post‐menopausal women (no exclusions specified)
Calcitonin
Psimenou 2002 (adults)	‐‐	BMD	Calcitonin	200 IU/d	‐‐	12 months	Low BMD; mean T‐score < ‐2.7 at baseline (no exclusions specified)
Nordal 1995 (adults)	‐‐	BMD	Calcitonin	200 IU/d	At transplantation	12 months	Inclusions and exclusions not specified. Incident population
Ugur 2000 (adults)	‐‐	BMD	Calcitonin	200 IU alternate days	> 12 months	12 months	T‐score < ‐1; transplantation > 12 months (no exclusions specified)
El‐Husseini 2004 (children and adolescents)	Living	BMD	Calcitonin	200 IU/d	48 months on average	12 months	T‐score ≤ ‐1 (excluded if anticonvulsant therapy or thiazide diuretic treatment)
El‐Husseini 2005a (children and adolescents)	‐‐	BMD	Calcitonin	200 IU/d	‐‐	12 months	kidney transplant recipients with low BMD (Z‐score ≤ ‐1) (no exclusions specified)
Potassium
Starke 2012 (adults)	Living and deceased	BMD and bone histomorphometry	Potassium citrate or potassium chloride	Titrated to achieve bicarbonate > 24 mmol/L	3 months to 8 years	12 months	Transplantation > 3 months and < 8 years; venous serum bicarbonate concentration < 24 mmol/L; stable graft function; eGFR > 30 mL/min/1.73 m² (excluded if acute rejection episodes; severe physical limitation; psychiatric disorder; malignancy; catabolic state due to systemic illness; acute systemic infection; pregnancy)
Ultraviolet light (UVB)
Praditpornsilpa 2014 (unknown)	‐‐	iPTH	UVB treatment	Initiated at dose of 700 mJ/cm² and the total accumulation dose was 6,952 mJ/cm² in 7th weeks	‐‐	‐‐	Kidney transplant recipients (no exclusions specified)

Bisphosphonate compared to placebo or no treatment for preventing bone disease in kidney transplant recipients
Patient or population: preventing bone disease in kidney transplant recipients  Setting: Primary or secondary prevention (no bone disease or fracture/low bone density or previous fracture)  Intervention: bisphosphonate  Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with placebo or no treatment	Risk with Bisphosphonate	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Fracture	95 per 1,000	59 per 1,000  (36 to 96)	RR 0.62  (0.38 to 1.01)	765 (13)	⊕⊕⊝⊝  LOW ^{1 2}
Acute graft rejection	404 per 1,000	282 per 1,000  (222 to 359)	RR 0.70  (0.55 to 0.89)	470 (7)	⊕⊕⊝⊝  LOW ^{1 3}
Death (all causes)	33 per 1,000	33 per 1,000  (11 to 93)	RR 0.98  (0.34 to 2.80)	597 (10)	⊕⊝⊝⊝  VERY LOW ^{1 2 4}
Cardiovascular death	13 per 1,000	4 per 1,000  (0 to 96)	RR 0.33  (0.01 to 7.58)	150 (3)	⊕⊝⊝⊝  VERY LOW ^{1 2 4}
Bone pain	133 per 1,000	27 per 1,000  (5 to 124)	RR 0.20  (0.04 to 0.93)	153 (3)	⊕⊕⊝⊝  LOW ^{1 2}
Spinal deformity	333 per 1,000	193 per 1,000  (87 to 437)	RR 0.58  (0.26 to 1.31)	72 (1)	⊕⊝⊝⊝  VERY LOW ^{1 5}
Hypocalcaemia	0 per 1,000	0 per 1,000  (0 to 0)	RR 5.59  (1.00 to 31.06)	207 (4)	⊕⊝⊝⊝  VERY LOW ^{1 2 4}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Vitamin D compared to placebo or no treatment for preventing bone disease in kidney transplant recipients
Patient or population: preventing bone disease in kidney transplant recipients  Setting: Primary or secondary prevention (no bone disease or fracture/low bone density or previous fracture)  Intervention: Vitamin D  Comparison: placebo or no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with placebo or no treatment	Risk with Vitamin D	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Fracture	7 per 1,000	7 per 1,000  (1 to 61)	RR 0.96  (0.10 to 8.94)	299 (5)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
Acute graft rejection	89 per 1,000	87 per 1,000  (46 to 165)	RR 0.98  (0.52 to 1.86)	385 (5)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
Death (all causes)	60 per 1,000	30 per 1,000  (2 to 556)	RR 0.49  (0.03 to 9.22)	232 (3)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
Cardiovascular death	43 per 1,000	25 per 1,000  (2 to 326)	RR 0.57  (0.04 to 7.57)	232 (3)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
Bone pain	0 per 1,000	0 per 1,000  (0 to 0)	not estimable	40 (1)	⊕⊝⊝⊝  VERY LOW ^{1 5}
Graft loss	37 per 1,000	4 per 1,000  (0 to 74)	RR 0.11  (0.01 to 2.01)	220 (3)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Date	Event	Description
12 June 2019	New citation required but conclusions have not changed	42 new studies added
12 June 2019	New search has been performed	Updated search and review findings using search date 16 May 2019

Date	Event	Description
13 August 2009	Amended	Contact details updated.
9 October 2008	Amended	Converted to new review format.
30 April 2007	New citation required and conclusions have changed	Substantive amendment

Database	Search strategy
CENTRAL	MeSH descriptor Kidney Transplantation, this term only in MeSH products (kidney or renal) next (transplant* or recipient):ti,ab,kw in Clinical Trials (#1 OR #2) (vitamin d):ti,ab,kw in Clinical Trials ("vitamin d3"):ti,ab,kw in Clinical Trials alfacalcidol:ti,ab,kw in Clinical Trials cholecalciferol:ti,ab,kw in Clinical Trials ergocalciferol:ti,ab,kw in Clinical Trials hydroxycholecalciferol:ti,ab,kw in Clinical Trials hydroxyvitamin:ti,ab,kw in Clinical Trials (dihydroxyvitamin):ti,ab,kw calcifediol:ti,ab,kw calcitriol:ti,ab,kw in Clinical Trials (#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13) MeSH descriptor Diphosphonates explode all trees in MeSH products alendron:ti,ab,kw in Clinical Trials clodron:ti,ab,kw in Clinical Trials etidron:ti,ab,kw in Clinical Trials ibandron:ti,ab,kw in Clinical Trials incadron:ti,ab,kw in Clinical Trials medron:ti,ab,kw in Clinical Trials olpadron:ti,ab,kw in Clinical Trials pamidronate:ti,ab,kw in Clinical Trials risedronate:ti,ab,kw in Clinical Trials tiludron:ti,ab,kw in Clinical Trials zoledron:ti,ab,kw in Clinical Trials biphosphonat:ti,ab,kw in Clinical Trials diphosphonat:ti,ab,kw in Clinical Trials MeSH descriptor Calcitonin, this term only in MeSH products calcitonin:ti,ab,kw in Clinical Trials calcitrin:ti,ab,kw in Clinical Trials (#15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31) MeSH descriptor Gonadal Hormones explode all trees in MeSH products MeSH descriptor Testosterone explode all trees in MeSH products testosterone:ti,ab,kw in Clinical Trials MeSH descriptor Estrogens explode all trees in MeSH products estrogen:ti,ab,kw in Clinical Trials oestrogen:ti,ab,kw in Clinical Trials MeSH descriptor Estradiol explode all trees in MeSH products hormone replacement therap:ti,ab,kw in Clinical Trials hrt or ert:ti,ab.kw in Clinical Trials (#33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41) MeSH descriptor Calcium, this term only in MeSH products MeSH descriptor Calcium Compounds explode all trees in MeSH products (calcium):ti,ab,kw in Clinical Trials and Methods Studies vitamin supplem in Clinical Trials (#43 OR #44 OR #45 OR #46) MeSH descriptor Vitamin D explode all trees MeSH descriptor Bone Density Conservation Agents explode all trees (#14 OR #32 OR #42 OR #47 OR #48 OR #49) (#3 AND #50)
MEDLINE	kidney transplantation/ exp Vitamin D/ vitamin d.tw. vitamin d3.tw. alfacalcidol$.tw. cholecalciferol$.tw. ergocalciferol$.tw. hydroxycholecalciferol$.tw. hydroxyvitamin$.tw. dihydroxyvitamin$.tw. calcifediol.tw. calcitriol.tw. or/2‐12 exp Diphosphonates/ alendron$.tw. clodron$.tw. etidron$.tw. ibandron$.tw. Incadron$.tw. Medron$.tw. Olpadron$.tw. Pamidron$.tw. Risedron$.tw. Tiludron$.tw. Zoledron$.tw. biphosphonat$.tw. diphosphonat$.tw. Calcitonin/ calcitonin.tw. calcitrin.tw. or/14‐30 exp Gonadal Hormones/ exp testosterone/ exp estrogens/ estradiol/ testosterone.tw. estrogen$.tw. oestrogen$.tw. exp Selective Estrogen Receptor Modulators/ tamoxifen.tw. raloxifene.tw. toremifene.tw. clomiphene.tw. exp Anabolic Agents/ (anabolic adj3 agent$).tw. anabolic steroid$.tw. nandrolone.tw. hormone replacement therap$.tw. (hrt or ert).tw. or/32‐49 calcium/ exp calcium compounds/ calcium.tw. vitamin supplem$.tw. exp Fluorides/ fluoride$.tw. or/51‐56 bone density conservation agents/ or/13,31,50,57‐58 and/1,59
EMBASE	exp kidney transplantation/ exp Vitamin D/ vitamin d.tw. vitamin d3.tw. alfacalcidol$.tw. cholecalciferol$.tw. ergocalciferol$.tw. hydroxycholecalciferol$.tw. hydroxyvitamin$.tw. dihydroxyvitamin$.tw. calcifediol.tw. calcitriol.tw. or/2‐12 exp bisphosphonic acid derivative/ alendron$.tw. clodron$.tw. etidron$.tw. ibandron$.tw. Incadron$.tw. Medron$.tw. Olpadron$.tw. Pamidron$.tw. Risedron$.tw. Tiludron$.tw. Zoledron$.tw. biphosphonat$.tw. diphosphonat$.tw. Calcitonin/ calcitonin.tw. calcitrin.tw. or/14‐30 exp sex hormones/ exp testosterone/ exp estrogens/ estradiol/ testosterone.tw. estrogen$.tw. oestrogen$.tw. hormone replacement therap$.tw. (hrt or ert).tw. or/32‐40 calcium/ exp calcium compounds/ calcium.tw. vitamin supplem$.tw. or/42‐45 Selective Estrogen Receptor Modulator/ exp Antiestrogen/ tamoxifen.tw. raloxifene.tw. toremifene.tw. Clomiphene.tw. Clomifene.tw. exp Anabolic Agent/ (anabolic adj3 agent$).tw. anabolic steroid$.tw. nandrolone.tw. exp Fluoride/ fluoride$.tw. or/47‐49 bone density conservation agent/ or/13,31,41,46,60 and/1,62

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation (minimisation may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub‐scales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Fracture	13	765	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.38, 1.01]
2 Acute graft rejection	7	470	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.55, 0.89]
3 Death	10		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 All causes	10	597	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.34, 2.80]
3.2 Cardiovascular	3	150	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.58]
4 Musculoskeletal disorders	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.1 Bone pain	3	153	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.04, 0.93]
4.2 Spinal deformity	1	72	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.26, 1.31]
5 Bone mineral density [g calcium/cm²]	13		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.1 Vertebral	13	579	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.01, 0.08]
5.2 Femoral neck	12	520	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.03, 0.07]
6 Presence of low bone turnover seen on bone histomorphometry	2	33	Risk Ratio (M‐H, Random, 95% CI)	1.67 [0.76, 3.64]
7 Serum parathyroid hormone	11	590	Mean Difference (IV, Random, 95% CI)	0.70 [‐0.62, 2.02]
8 Vascular calcification score	2	74	Std. Mean Difference (IV, Random, 95% CI)	‐0.00 [‐0.46, 0.46]
9 Proteinuria (urinary protein:creatinine ratio)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
10 Graft loss	7	403	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.27, 1.60]
11 Serum creatinine	12	504	Mean Difference (IV, Random, 95% CI)	2.18 [‐7.78, 12.15]
12 eGFR [mL/min/1.73 m²]	2	82	Mean Difference (IV, Random, 95% CI)	‐0.97 [‐17.62, 15.67]
13 Gastro‐oesophageal disorder	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
14 Gastrointestinal symptoms	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
14.1 Nausea	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
14.2 Vomiting	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
14.3 Diarrhoea	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
15 Hypercalcaemia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
16 Hypocalcaemia	4	207	Risk Ratio (M‐H, Random, 95% CI)	5.59 [1.00, 31.06]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Fracture	5	299	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.10, 8.94]
2 Acute graft rejection	5	385	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.52, 1.86]
3 Death	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
3.1 All causes	3	232	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.03, 9.22]
3.2 Cardiovascular	3	232	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.04, 7.57]
4 Musculoskeletal disorders	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1 Bone pain	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Bone mineral density [g calcium/cm²]	9		Mean Difference (IV, Random, 95% CI)	Subtotals only
5.1 Vertebral	9	377	Mean Difference (IV, Random, 95% CI)	0.02 [‐0.03, 0.07]
5.2 Femoral neck	7	292	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.07, 0.06]
6 Serum parathyroid hormone	6	340	Mean Difference (IV, Random, 95% CI)	‐1.74 [‐3.04, ‐0.44]
7 Proteinuria	2	245	Std. Mean Difference (IV, Random, 95% CI)	‐0.43 [‐1.24, 0.39]
8 Graft loss	3	220	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 2.01]
9 Serum creatinine	6	313	Mean Difference (IV, Random, 95% CI)	3.87 [‐3.64, 11.37]
10 eGFR [mL/min/1.73 m²]	6	449	Mean Difference (IV, Random, 95% CI)	3.96 [‐7.59, 15.52]
11 Hypercalcaemia	7	465	Risk Ratio (M‐H, Random, 95% CI)	2.09 [0.84, 5.22]
12 Fever	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13 Myocardial infarction	2	143	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.01, 7.68]
14 Stroke	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
15 Parathyroidectomy	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Fracture	4	153	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.06, 1.78]
2 Death	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.1 All causes	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Cardiovascular	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Musculoskeletal disorders	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1 Avascular bone necrosis	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Bone mineral density [g calcium/cm²]	2		Mean Difference (IV, Random, 95% CI)	Subtotals only
4.1 Vertebral	2	61	Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.10, 0.02]
4.2 Femoral neck	2	61	Mean Difference (IV, Random, 95% CI)	0.03 [‐0.08, 0.15]
5 Serum parathyroid hormone	2	61	Mean Difference (IV, Random, 95% CI)	0.88 [‐2.62, 4.38]
6 Graft loss	2	61	Risk Ratio (M‐H, Random, 95% CI)	0.19 [0.01, 3.63]
7 Serum creatinine	2	61	Mean Difference (IV, Random, 95% CI)	‐31.12 [‐141.96, 79.72]
8 Gastrointestinal symptoms	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
8.1 Vomiting	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9 Hypocalcaemia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Acute graft rejection	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Bone mineral density [g calcium/cm²]	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1 Lumbar spine	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Femoral neck	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Presence of low bone turnover on bone histomorphometry	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Serum creatinine	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Fracture	2	141	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.90]
2 Acute graft rejection	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Death	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1 All causes	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Musculoskeletal disorders	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1 Bone pain	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Avascular bone necrosis	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Bone mineral density [g calcium/cm²]	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1 Vertebral	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Femoral neck	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
6 Presence of low bone turnover on bone histomorphometry	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
7 Serum parathyroid hormone	2	188	Mean Difference (IV, Random, 95% CI)	‐0.32 [‐2.94, 2.31]
8 Graft loss	2	141	Risk Ratio (M‐H, Random, 95% CI)	2.38 [0.26, 22.12]
9 Serum creatinine	3	218	Mean Difference (IV, Random, 95% CI)	10.24 [‐0.05, 20.53]
10 eGFR [mL/min/1.73 m²]	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
11 Gastro‐oesophageal disorder	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
12 Hypercalcaemia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Fracture	2	61	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.02, 8.08]
2 Musculoskeletal disorders	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.1 Bone pain	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Bone mineral density [g calcium/cm²]	3		Mean Difference (IV, Random, 95% CI)	Subtotals only
3.1 Vertebral	2	61	Mean Difference (IV, Random, 95% CI)	0.10 [‐0.10, 0.31]
3.2 Femoral neck	3	104	Mean Difference (IV, Random, 95% CI)	0.06 [0.02, 0.11]
4 Serum parathyroid hormone	2	61	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.61, 0.63]
5 Graft loss	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6 Serum creatinine	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
7 Gastrointestinal symptoms	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
7.1 Diarrhoea	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Death	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 All causes	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 eGFR [mL/min/1.73 m²]	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serum parathyroid hormone	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2 eGFR [mL/min/1.73 m²]	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Fracture: incident or prevalent patients	13	765	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.37, 0.97]
1.1 Incident patients	9	583	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.37, 1.05]
1.2 Prevalent patients	4	182	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.13, 1.77]
2 Fracture: adults and children	13	765	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.37, 0.97]
2.1 Adults	12	735	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.37, 1.00]
2.2 Children	1	30	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.58]
3 Fracture: treatment duration	13	765	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.37, 0.97]
3.1 6 months or less	1	19	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.19, 6.34]
3.2 More than 6 months	12	746	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.34, 0.94]
4 Fracture: primary or secondary prevention	13	765	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.37, 0.97]
4.1 Primary	9	582	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.35, 1.02]
4.2 Secondary	4	183	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.17, 1.97]
5 Fracture: surveillance versus non‐systematic assessment	13	765	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.37, 0.97]
5.1 Surveillance	6	519	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.35, 1.01]
5.2 Non‐systematic	7	246	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.19, 2.04]
6 Fracture: baseline bone mineral density	13	765	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.38, 1.01]
6.1 Low	4	183	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.17, 1.97]
6.2 Normal or not specified	9	582	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.37, 1.06]
7 Fracture: spinal or peripheral	13	765	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.38, 1.01]
7.1 Peripheral	2	60	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.04, 3.04]
7.2 Vertebral	7	578	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.36, 1.02]
7.3 Not specified	4	127	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.19, 6.34]
8 Fracture: high and low potency bisphosphonate	13	765	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.38, 1.01]
8.1 High potency	4	305	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.38, 1.29]
8.2 Low potency	9	460	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.23, 1.13]
9 Bone mineral density at vertebrae: drug potency	13	579	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.01, 0.08]
9.1 Low potency (clodronate, pamidronate, alendronate)	9	331	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.04, 0.11]
9.2 High potency (risedronate, ibandronate, zolendronate)	4	248	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.03, 0.10]

Methods	Study design: open‐label, parallel RCT Duration of study: January 2007 to November 2011 Duration of follow‐up: 1 year
Participants	Country: USA Setting: single centre Inclusion criteria: adults (≥ 18 years) receiving 1st or 2nd compatible kidney transplant and eligible for corticosteroid avoidance immunosuppression protocol (Mayo Clinic) Number: treatment group (51); control group (49) Mean age ± SD (years): treatment group (48.5 ± 10.3); control group (47.7 ± 10.0) Sex (M/F): tre47atment group (33/18); control group (33/16) Exclusion criteria: prior hypocalcaemia; total 25‐hydroxyvitamin D < 10 ng/mL; multiple organ transplantation; receiving calcimimetic agent prior to transplant
Interventions	Treatment group Paricalcitol (oral): 1 µg/d on day 3 post transplant, increased to 2 µg/d on day 15 post transplant if no hypercalcaemia developed Control group No treatment Co‐interventions Calcium (oral): 500 mg twice daily
Outcomes	Hyperparathyroidism 1 year post transplant (defined as the need for parathyroidectomy during the 1st year or PTH > 65 pg/mL in the absence of hypocalcaemia at the end of the 1st year) T‐score at spine and hip Death or graft loss Acute graft rejection Kidney outcomes: mean GFR, mean urine total protein excretion, degree of interstitial fibrosis on biopsy
Notes	Funding source: "This trial was funded by Abbott Laboratories (Abbot Park, IL) through an investigator initiated research grant. The sponsor had access to the data but did not influence the conduct of the study. Mayo Clinic and not the industry sponsor supported the study’s consultant statistician."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation tables generated by statistician
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement for primary study endpoint (hyperparathyroidism)
Incomplete outcome data (attrition bias)   All outcomes	High risk	13/100 participants were not included in full follow‐up. Although the proportion were similar in each arm, the overall proportion indicated high risk of bias
Selective reporting (reporting bias)	Low risk	The study reported patient‐level outcomes including death, graft function, and adverse events
Other bias	Low risk	Study appears free of other biases

Methods	Study design: parallel RCT Duration of study: not reported Duration of follow‐up: 24 weeks
Participants	Country: Slovenia Setting: single centre Inclusion criteria: kidney transplant recipients at least 3 months' post transplant with UPCR ≥ 20 mg/mmol despite optimisation of RAAS blockade during run‐in phase Number: treatment group (83); control group (85) Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group Paricalcitol: 2 µg/d Control group Placebo Co‐interventions Not reported
Outcomes	UPCR UACR IL6 and TGF‐beta plasma concentrations
Notes	Abstract‐only publication, no full‐text publication identified Funding source: not reported Trial registration: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blinded
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	High risk	Patient‐level outcomes including adverse events were not systematically reported
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: open label, parallel RCT Study duration: not reported Duration of follow‐up: 2 years
Participants	Country: France Setting: not reported Inclusion criteria: kidney transplant recipients (cadaveric) Number: 24 (no numbers for groups) Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: nor reported
Interventions	Treatment group 25OH Vitamin D: 50 µg/d Control group No treatment Co‐interventions Not reported
Outcomes	Plasma calcium, phosphate, alkaline phosphatase, Creatinine PTH Calcitonin Vitamin D metabolites
Notes	Abstract‐only publication with no extractable data; no full‐text publication identified after 10 years Funding source not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	High risk	Data unable to be meta‐analysed
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: parallel group Duration of study: not reported Duration of follow‐up: 36 months
Participants	Country: Italy Setting: single centre Inclusion criteria: postmenopausal kidney transplant recipients Number: treatment group (29); control group (29) Age range (years): treatment group (47 to 57); control group (48 to 58) Sex (M/F): treatment group (0/29); control group (0/29) Exclusion criteria: not reported
Interventions	Treatment group Uninterrupted percutaneous 17 β‐estradiol: 50 µg Medroxyprogesterone: 10 mg/d on days 16 to 28 of cycle Control group 1,25 dihydroxyvitamin D3 (oral): 0.25 µg/d
Outcomes	BMD at lumbar spine by DEXA
Notes	Abstract‐publication only Funding source: not reported Trial registration: not applicable as published before end of 2005
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Treatments were sufficiently different that blinding was unlikely
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	21/58 participants did not complete follow‐up
Selective reporting (reporting bias)	High risk	Patient‐centred outcomes not captured or reported systematically
Other bias	Unclear risk	Insufficient data to perform adjudication

PERMALINK

Interventions for preventing bone disease in kidney transplant recipients

Suetonia C Palmer

Edmund YM Chung

David O McGregor

Friederike Bachmann

Giovanni FM Strippoli

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

1. Published guidelines for bone disease in kidney transplant recipients.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Cross‐over studies

Studies with more than two interventions

Cluster randomised studies

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Primary efficacy outcome

Primary safety outcome

Secondary outcomes

Results

Description of studies

Results of the search

1.

Original review (2004)

Review update (2007)

Review update (2019)

Included studies

2. Treatment timing and duration.

Study comparisons

Study outcomes

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Random sequence generation

Allocation concealment

Blinding

Blinding of participants and investigators

Blinding of outcome assessment

Incomplete outcome data

Selective reporting

Other potential sources of bias

Methods	Study design: double‐blind, placebo‐controlled RCT Duration of study: not reported Duration of follow‐up: 52 weeks
Participants	Country: Belgium, Norway, Italy, France, Denmark, Poland, USA, Switzerland Setting: multicentre Inclusion criteria: kidney transplant recipient ≥18 years of age (between 9 weeks and 24 months post transplant) with stable kidney function (eGFR ≥ 30 mL/min/1.73 min²), serum calcium >2.63 mmol/L, and iPTH >100 pg/mL Number: treatment group (57); control group (57) Mean age ± SD (years): treatment group (53.0 ± 10.7); control group (51.7 ± 9.9) Sex (M/F): treatment group (31/26); control group (32/25) Exclusion criteria: not reported
Interventions	Treatment group Cinacalcet (oral): 30 mg daily titrated every 4 weeks to maximum 180 mg/d based on iPTH level Control group Placebo Co‐interventions Not reported
Outcomes	Achievement of serum calcium < 2.55 mmol/L BMD at femoral neck, lumbar spine, distal radius Serum calcium, phosphate, iPTH, FGF‐23 Biomarkers of bone turnover Kidney function (eGFR) and urinary calcium Adverse events of medications
Notes	Funding source: " This study was funded by Amgen Inc. K Cooper, H Deng and S Yue are employees and stockholders of Amgen Inc. P Evenepoel has been a member of advisory boards, received grant support and speaker’s fees from Amgen." Trial registration: not reported (Amgen protocol 20062007)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded placebo‐controlled trial
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	10/114 discontinued study with equal attrition in both groups
Selective reporting (reporting bias)	Low risk	Patient‐level outcomes reported as expected
Other bias	High risk	Funded by Amgen; 3 authors are employees of Amgen

Methods	Study design: parallel‐group, placebo‐controlled RCT Duration of study: not reported Duration of follow‐up: 48 months
Participants	Country: UK Setting: single centre Inclusion criteria: adult male cadaveric kidney transplant recipients Number: treatment group (14); control group (12) Mean age, range (years): treatment group (53, 23 to 66); control group (50, 23 to 74) Sex (M/F): all male Exclusion criteria: not reported
Interventions	Treatment group Parenteral pamidronate: 0.5 mg/kg in saline preoperatively and 1 month postoperatively Control group Placebo: parenteral saline
Outcomes	Serum calcium, phosphate BMD by DEXA at L2‐L4 and femoral neck
Notes	Funding source: not reported Trial registration: not applicable as published before end of 2005
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	High risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not reported in sufficient detail. Intervention and comparison were different and not described as identical.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	1 patient in the treatment group did not complete study (3rd transplant)
Selective reporting (reporting bias)	High risk	Patient‐centred outcomes including adverse events were not reported systematically
Other bias	Low risk	No additional threats to validity identified.

Methods	Study design: no treatment‐control, parallel RCT Duration of study: not reported Duration of follow‐up: 12 months
Participants	Country: Italy Setting: single centre Inclusion criteria: deceased donor kidney transplant recipients, lag time from transplant > 6 months Number: treatment group (20); control group (20) Mean age ± SD (years): treatment group (57 ± 11); control group (55 ± 13) Sex (M/F): treatment group (13/7); control group (12/8) Time since transplant (months): treatment group (71 ± 38); control group (76 ± 53) Exclusion criteria: previous treatment with bisphosphonate or other antiresorptive drugs; history of major upper GI illness such as peptic ulcer, oesophagitis or severe dyspepsia
Interventions	Treatment group Alendronate: 10 mg daily Control group No treatment Co‐interventions Vitamin D or analogue and calcium
Outcomes	SCr and calcium BMD by DEXA at lumbar spine and femoral neck
Notes	Funding source: Grant 9906195523‐MURST and ICS 030.8/RF99.43 of the Italian Ministry of Health Trial registration: not applicable as no published before end of 2005
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation list
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Unblinded
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	2/20 patients in control group did not complete study follow up and were not included in analyses
Selective reporting (reporting bias)	High risk	Patient‐centred outcomes not captured or reported systematically
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: placebo‐controlled, parallel RCT Duration of study: not reported Duration of follow‐up: 32 months
Participants	Country: Austria Setting: multicentre (no of sites not reported) Inclusion criteria: successful deceased donor, kidney transplantation of 1st or 2nd transplant; normocalcaemia, SCr < 0.18 mmol/L at 2 weeks; baseline bone biopsy demonstrates no adynamic bone disease Number: treatment group (10); control group (10) Mean age ± SE (years): treatment group (55 ± 18); control group (49 ± 16) Sex (M/F): treatment group (6/4); control group (6/4) Exclusion criteria: previous or current treatment with calcitonin or bisphosphonate or with hypocalcaemia
Interventions	Treatment group 1,25 dihydroxyvitamin D3 (oral): 0.25 µg/d Control group Placebo Co‐interventions Not reported
Outcomes	BMD by DEXA at lumbar spine (L1‐L4) and femoral neck Bone histomorphometry measured and calculated according to the American Society of Bone and Mineral Research (ASBMR) SCr Incidence of acute graft rejection
Notes	Funding source: Research grant from Novartis Trial registration: not applicable as published before end of 2005
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Patients treated with intervention or placebo, but nature of placebo not fully described
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Bone biopsy histological analysis conducted by pathologist who was unaware of treatment allocation. Assessment of fracture not described
Incomplete outcome data (attrition bias)   All outcomes	High risk	Outcome data reported for 13/28 participants
Selective reporting (reporting bias)	Low risk	Patient‐centred outcomes reported
Other bias	High risk	Funded by Novartis

Methods	Setting: active comparator, parallel RCT Duration of study: November 1997 Duration of follow‐up: 12 months
Participants	Country: Canada Setting: multicentre (2 sites) Inclusion criteria: kidney transplant recipients, stable kidney function, estimated GFR > 35 mL/min, T‐score < ‐1 at either lumbar spine or femur Number: treatment group (57); control group (60) Mean age at transplantation ± SD (years): treatment group (44.8 ± 11.6); control group (45.9 ± 10.8) Mean time since transplantation ± SD (years): treatment group (7.1 ± 5.2); control group (9.6 ± 6.8) Sex (M/F): treatment group (34/12); control group (37/14) Exclusion criteria: previous treatment for bone disease, recent oesophagitis or gastritis
Interventions	Treatment group Alendronate (oral): 10 mg/d Control group Calcitriol (oral): 0.25 µg/d Co‐interventions Not reported
Outcomes	BMD by DEXA at lumbar vertebrae (L2‐L4) and proximal femur SCr
Notes	Funding source: not reported Trial registration: not applicable as published before end of 2005
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	20/117 participants did not complete study
Selective reporting (reporting bias)	High risk	Patient‐centred outcomes not reported systematically
Other bias	High risk	Imbalanced time since transplantation between groups at baseline

Methods	Study design: no treatment‐controlled, parallel RCT Duration of study: not reported Duration of follow‐up: 12 months
Participants	Country: Turkey Setting: single centre Inclusion criteria: non‐diabetic kidney transplant recipients Number: treatment group 1 (8); treatment group 2 (8); control group (8) Mean age ± SD (years): treatment group 1 (34.4 ± 8.9); treatment group 2 (40.5 ± 8.1); control group (35.5 ± 8.4) Sex (M/F): treatment group 1 (6/2); treatment group 2 (5/3); control group (6/2) Time since transplant (months): treatment group 1 (48.7 ± 50.1); treatment group 2 (47.4 ± 46.4); control group (41.5 ± 37.1) Exclusion criteria: duration of transplant < 12 months, SCr > 0.18 mmol/L or ≥ 20% increment during the preceding 12 months or prednisolone dosage that changed during the study period; hyperparathyroidism; gonadal insufficiency; parathyroidectomy or other cause of osteoporosis
Interventions	Treatment group 1 Alendronate (oral): 5 mg/d Treatment group 2 Calcitonin (intranasal): 100 µL alternate days, stopped 1 month of every 3 months Control group No treatment Co‐interventions Calcium carbonate, increased if hypocalcaemia. Participants did not receive fluoride, vitamin D, or any hormonal therapy
Outcomes	SCr, calcium and phosphorus BMD by DEXA of lumbar vertebrae and femoral neck
Notes	Funding source: not reported Trial registration: not applicable as study published before end of 2005
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Unblinded study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	11/24 participants were not included in final analysis
Selective reporting (reporting bias)	High risk	Patient‐centred outcomes not reported systematically
Other bias	Low risk	No additional threats to validity identified

Methods	Study design: no treatment‐controlled, open‐label RCT Duration of study: 2003 to 2007 Duration of follow‐up: 6 months
Participants	Country: China Setting: single centre Inclusion criteria: kidney transplant recipient with stable kidney function, SCr < 221 µmol/L, >1 year after transplant, T‐score < ‐1 Number: treatment group (23); control group (23) Mean age ± SD (years): treatment group (39.4 ± 17.3); control group (40.2 ± 18.5) Sex (M/F): treatment group (10/13); control group (9/14) Exclusion criteria: DM; liver disease; chronic GI disease; intake of vitamin D or analogues during the post‐transplant period
Interventions	Treatment group Alendronate (oral): 70 mg/week Control group No treatment Co‐interventions Calcium carbonate (oral) 800 mg/d Calcitriol (oral): 0.25 µg/d
Outcomes	Change in BMD of lumbar spine and femoral neck Serum calcium, phosphate Biomarkers of bone turnover
Notes	Funding source: not reported Trial registration: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Not reported. Unlikely to be blinded due to differences in medication regimens
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	High risk	Patient important outcomes not reported systematically
Other bias	Low risk	No additional threats to validity identified

Methods	Study design: parallel RCT Study duration: not reported Duration of follow‐up: 1 year
Participants	Country: Venezuela Setting: not reported Inclusion criteria: long‐term kidney transplant recipients with severe osteopenia or osteoporosis Number: 24 (numbers per group not reported) Mean age ± SD (years): treatment group (42.3 ± 6.1); control group (37.1 ± 9.1) Sex (M/F): all male Exclusion criteria: not reported
Interventions	Treatment group Pamidronate (oral): 200 mg twice/d Control group Placebo Co‐interventions Not reported
Outcomes	BMD Serum calcium, phosphorus, iPTH Adverse events
Notes	Abstract‐only publication with no extractable data; no full‐text publication identified after 10 years Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	High risk	Data unable to be meta‐analysed
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: RCT (design unclear) Study duration: not reported Duration of follow‐up: 6 and 12 months
Participants	Country: Japan Setting: single centre Inclusion criteria: kidney transplant recipients > 16 years with good kidney function Number: 9 (numbers per group not reported) Age: not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group 1 Alfacalcidol: dose not reported Treatment group 2 Alendronate: dose not reported Co‐interventions Not reported
Outcomes	BMD Serum calcium, alkaline phosphatase
Notes	Abstract‐only publication with no extractable data; no full‐text publication identified after 10 years Funding source not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	High risk	Data unable to be meta‐analysed
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	judgementCountry: Study design: Prospective randomised uncontrolled parallel‐group randomised trial Duration of study: not reported Duration of follow‐up: 24 weeks
Participants	Country: Argentina Setting: single centre Inclusion criteria: kidney transplant recipients; eGFR < 60 mL/min; secondary hyperparathyroidism Number: treatment group (6); control group (6) Mean age ± SD (years): treatment group (57.5 ± 8); control group (52.3 ± 6) Sex (M/F): not reported Exclusion criteria: GFR > 60 mL/min; PTH > 110 pg/mL; corrected calcium >10.5 mg/dL; serum phosphorus > 5.5 mg/dL
Interventions	Treatment group Paricalcitol (oral): uncertain dose (error in abstract) Control group Calcitriol (oral): 0.25 mg/d Co‐interventions Not reported
Outcomes	PTH
Notes	Abstract‐only publication; full‐text publication not identified Funding source: not reported Trial registration: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients included in outcome assessment at 24 weeks
Selective reporting (reporting bias)	High risk	Patient important outcomes were not all reported in systematic way
Other bias	Unclear risk	Insufficient information to permit judgement